Estrogen receptor modulators and uses thereof

ABSTRACT

Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

RELATED APPLICATIONS

This application is a divisional patent application of co-pending U.S.application Ser. No. 13/234,035 entitled “ESTROGEN RECEPTOR MODULATORSAND USES THEREOF” filed Sep. 15, 2011, which claims the benefit of U.S.provisional patent application No. 61/383,659 entitled “ESTROGENRECEPTOR MODULATORS AND USES THEREOF” filed on Sep. 16, 2010; U.S.provisional patent application No. 61/410,727 entitled “ESTROGENRECEPTOR MODULATORS AND USES THEREOF” filed on Nov. 5, 2010; U.S.provisional patent application No. 61/446,967 entitled “ESTROGENRECEPTOR MODULATORS AND USES THEREOF” filed on Feb. 25, 2011; UnitedKingdom Patent Application No. 11 04288.4 entitled “ESTROGEN RECEPTORMODULATORS AND USES THEREOF” filed on Mar. 15, 2011; each of which isincorporated by reference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds, including pharmaceutically acceptablesalts, solvates, metabolites, prodrugs thereof, methods of making suchcompounds, pharmaceutical compositions comprising such compounds, andmethods of using such compounds to treat, prevent or diagnose diseasesor conditions that are estrogen sensitive, estrogen receptor dependentor estrogen receptor mediated.

BACKGROUND OF THE INVENTION

The estrogen receptor (“ER”) is a ligand-activated transcriptionalregulatory protein that mediates induction of a variety of biologicaleffects through its interaction with endogenous estrogens. Endogenousestrogens include 17β-estradiol and estrones. ER has been found to havetwo isoforms, ER-α and ER-β. Estrogens and estrogen receptors areimplicated in a number of diseases or conditions, such as breast cancer,ovarian cancer, colon cancer, prostate cancer, endometrial cancer,uterine cancer, as well as others diseases or conditions.

SUMMARY OF THE INVENTION

In one aspect, presented herein are compounds of Formula (I), or apharmaceutically acceptable salt, or N-oxide thereof, that diminish theeffects of estrogens with estrogen receptors and/or lower theconcentrations of estrogen receptors, and therefore, are useful asagents for the treatment or prevention of diseases or conditions inwhich the actions of estrogens and/or estrogen receptors are involved inthe etiology or pathology of the disease or condition or contribute toat least one symptom of the disease or condition and wherein suchactions of estrogens and/or estrogen receptors are undesirable. In someembodiments, compounds disclosed herein are estrogen receptor degradercompounds.

In one aspect, the compound of Formula (I), or a pharmaceuticallyacceptable salt, or N-oxide thereof, is useful for the treatment ofER-related diseases or conditions including, but not limited to,ER-αdysfunction associated with cancer (e.g. bone cancer, breast cancer,colorectal cancer, endometrial cancer, prostate cancer, ovarian anduterine cancer), leiomyoma (e.g. uterine leiomyoma), central nervoussystem (CNS) defects (e.g. alcoholism, migraine), cardiovascular systemdefects (e.g. aortic aneurysm, susceptibility to myocardial infarction,aortic valve sclerosis, cardiovascular disease, coronary artery disease,hypertension), hematological system defects (e.g. deep vein thrombosis),immune and inflammation diseases (e.g. Graves' Disease, arthritis,multiple sclerosis, cirrhosis), susceptibility to infection (e.g.hepatitis B, chronic liver disease), metabolic defects (e.g. bonedensity, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia,osteoporosis), neurological defects (e.g. Alzheimer's disease,Parkinson's disease, migraine, vertigo), psychiatric defects (e.g.anorexia nervosa, attention deficity hyperactivity disorder (ADHD),dementia, major depressive disorder, psychosis) and reproductive defects(e.g. age of menarche, endometriosis, infertility).

In one aspect, described herein are compounds of Formula (I),pharmaceutically acceptable salts, solvates, N-oxides, metabolites andprodrugs thereof. Compounds of Formula (I) are estrogen receptormodulators. In some embodiments, the compound of Formula (I) is anestrogen receptor antagonist. In some embodiments, the compound ofFormula (I) is an estrogen receptor degrader. In some embodiments, thecompound of Formula (I) is an estrogen receptor antagonist as well as anestrogen receptor degrader. In some embodiments, the compound of Formula(I) displays miminal or no estrogen receptor agonist activity. In someembodiments, in the context of treating cancers, the compound of Formula(I) offers improved therapeutic activity characterized by complete orlonger-lasting tumor regression, a lower incidence or rate ofdevelopment of resistance to treatment, and/or a reduction in tumorinvasiveness.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, or N-oxide thereof:

-   -   wherein,    -   Z is —OH or —OR¹⁰;    -   R² is C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄deuteroalkyl,        C₃-C₆cycloalkyl, or —C₁-C₄alkylene-W;        -   W is hydroxy, halogen, CN, C₁-C₄alkyl, C₁-C₄haloalkyl,            C₁-C₄alkoxy, C₁-C₄haloalkoxy, or C₃-C₆cycloalkyl;    -   each R³ is independently halogen, C₁-C₄alkyl, or        C₁-C₄-fluoroalkyl;    -   each R⁴ is independently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰,        C₁-C₄alkyl, C₁-C₄-fluoroalkyl, or C₁-C₄heteroalkyl;    -   each R⁵ is independently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰,        C₁-C₄alkyl, C₁-C₄-fluoroalkyl, or C₁-C₄heteroalkyl;    -   R⁶ is H, C₁-C₄alkyl, or halogen; R⁷ is H, C₁-C₄alkyl, or        halogen;    -   R⁹ is H, C₁-C₆alkyl, C₁-C₆-fluoroalkyl, or C₃-C₆cycloalkyl;    -   R¹⁰ is C₁-C₆alkyl;    -   m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable salt, orN-oxide thereof, has the structure of Formula (II), or apharmaceutically acceptable salt, or N-oxide thereof.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is a compound described in Table 1, or apharmaceutically acceptable salt thereof.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Compounds disclosed herein are estrogen receptor modulators. In someembodiments, compounds disclosed herein have high specificity for theestrogen receptor and have desirable, tissue-selective pharmacologicalactivities. Desirable, tissue-selective pharmacological activitiesinclude, but are not limited to, ER antagonist activity in breast cellsand minimal or no ER agonist activity in uterine cells. In someembodiments, compounds disclosed herein are estrogen receptor degradersthat display full estrogen receptor antagonist activity with negligibleor minimal estrogen receptor agonist activity.

In some embodiments, compounds disclosed herein are estrogen receptordegraders. In some embodiments, compounds disclosed herein are estrogenreceptor antagonists. In some embodiments, compounds disclosed hereinhave minimal or negligible estrogen receptor agonist activity.

In some embodiments, presented herein are compounds selected from activemetabolites, tautomers, pharmaceutically acceptable solvates,pharmaceutically acceptable salts or prodrugs of a compound of Formula(I).

Also described are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, or N-oxide thereof. In someembodiments, the pharmaceutical composition also contains at least onepharmaceutically acceptable inactive ingredient. In some embodiments,the pharmaceutical composition is formulated for intravenous injection,subcutaneous injection, oral administration, or topical administration.In some embodiments, the pharmaceutical composition is a tablet, a pill,a capsule, a liquid, a suspension, a gel, a dispersion, a suspension, asolution, an emulsion, an ointment, or a lotion.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutically active agents selected from:corticosteroids, anti-emetic agents, analgesics, anti-cancer agents,anti-inflammatories, kinase inhibitors, antibodies, HSP90 inhibitors,histone deacetylase (HDAC) inhibitors, poly ADP-ribose polymerase (PARP)inhibitors, and aromatase inhibitors.

In some embodiments, provided herein is a method comprisingadministering a compound of Formula (I), or a pharmaceuticallyacceptable salt, or N-oxide thereof to a human with a diseases orcondition that is estrogen sensitive, estrogen receptor meditated orestrogen receptor dependent. In some embodiments, the human is alreadybeing administered one or more additional therapeutically active agentsother than a compound of Formula (I), or a pharmaceutically acceptablesalt, or N-oxide thereof. In some embodiments, the method furthercomprises administering one or more additional therapeutically activeagents other than a compound of Formula (I), or a pharmaceuticallyacceptable salt, or N-oxide thereof.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (I), or a pharmaceuticallyacceptable salt, or N-oxide thereof are selected from: corticosteroids,anti-emetic agents, analgesics, anti-cancer agents, anti-inflammatories,kinase inhibitors, antibodies, HSP90 inhibitors, histone deacetylase(HDAC) inhibitors, and aromatase inhibitors.

In some embodiments, the methods further comprise administering to themammal radiation therapy. In certain embodiments, the compound of themethods is administered prior to or following surgery. In certainembodiments, the methods comprise administering to the mammal at leastone additional anti-cancer agent.

In some embodiments, there are provided methods of treating cancer in amammal comprising administering to the mammal a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, or N-oxide thereof. In certain embodiments, the canceris breast cancer, ovarian cancer, endometrial cancer, prostate cancer,uterine cancer, cervical cancer or lung cancer. In certain embodiments,the cancer is breast cancer. In certain embodiments, the cancer is ahormone dependent cancer. In certain embodiments, the cancer is anestrogen receptor dependent cancer. In certain embodiments, the canceris an estrogen-sensitive cancer. In certain embodiments, the cancer isresistant to anti-hormonal treatment. In certain embodiments, the canceris an estrogen-sensitive cancer or an estrogen receptor dependent cancerthat is resistant to anti-hormonal treatment. In some embodiments, theanti-hormonal treatment includes treatment with at least one agentselected from tamoxifen, fulvestrant, steroidal aromatase inhibitors,and non-steroidal aromatase inhibitors. In some embodiments, the methodsfurther comprise administering to the mammal radiation therapy. Incertain embodiments, the compound of the methods is administered priorto or following surgery. In certain embodiments, the methods compriseadministering to the mammal at least one additional anti-cancer agent.

In some embodiments, there are provided methods of treating hormonereceptor positive metastatic breast cancer in a postmenopausal womanwith disease progression following anti-estrogen therapy comprisingadministering to the woman an estrogen receptor degrading compound ofFormula (I), or a pharmaceutically acceptable salt, or N-oxide thereof.In some embodiments, the methods further comprise administering to themammal radiation therapy. In certain embodiments, the compound of themethods is administered prior to or following surgery. In certainembodiments, the methods comprise administering to the mammal at leastone additional anti-cancer agent.

In some embodiments, there are provided methods of treating a hormonaldependent benign or malignant disease of the breast or reproductivetract in a mammal comprising administering to the mammal an effectiveamount of a compound of Formula (I), a pharmaceutically acceptable salt,or N-oxide thereof. In certain embodiments, the benign or malignantdisease is breast cancer. In some embodiments, the methods furthercomprise administering to the mammal radiation therapy. In certainembodiments, the compound of the methods is administered prior to orfollowing surgery. In certain embodiments, the methods compriseadministering to the mammal at least one additional anti-cancer agent.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt, or N-oxide thereof is used to treat hormone receptorpositive metastatic breast cancer in a postmenopausal woman with diseaseprogression following anti-estrogen therapy. In some embodiments, thecompound is used to treat a hormonal dependent benign or malignantdisease of the breast or reproductive tract in a mammal.

Also provided is a method of reducing ER activation in a mammalcomprising administering to the mammal at least one compound having thestructure of Formula (I), or a pharmaceutically acceptable salt, orN-oxide thereof. In some embodiments, the method comprises reducing ERactivation in breast cells, ovarian cells, colon cells, prostate cells,endometrial cells, or uterine cells in the mammal. In some embodiments,the method of reducing ER activation in the mammal comprises reducingthe binding of estrogens to estrogen receptors in the mammal. In someembodiments, the method of reducing ER activation in the mammalcomprises reducing ER concentrations in the mammal.

In one aspect is the use of a compound of Formula (I), or apharmaceutically acceptable salt, or N-oxide thereof in the manufactureof a medicament for the treatment of diseases or conditions that areestrogen sensitive, estrogen receptor dependent or estrogen receptormediated. In some embodiments, the disease or condition is breastcancer, ovarian cancer, colon cancer, prostate cancer, endometrialcancer, or uterine cancer. In some embodiments, the disease or conditionis bone cancer, breast cancer, colorectal cancer, endometrial cancer,prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lungcancer, alcoholism, migraine, aortic aneurysm, susceptibility tomyocardial infarction, aortic valve sclerosis, cardiovascular disease,coronary artery disease, hypertension, deep vein thrombosis, Graves'Disease, arthritis, multiple sclerosis, cirrhosis, hepatitis B, chronicliver disease, bone density, cholestasis, hypospadias, obesity,osteoarthritis, osteopenia, osteoporosis, Alzheimer's disease,Parkinson's disease, migraine, vertigo, anorexia nervosa, attentiondeficit hyperactivity disorder (ADHD), dementia, major depressivedisorder, psychosis, age of menarche, endometriosis, or infertility in amammal. In some embodiments, the disease or condition is describedherein.

In some cases disclosed herein is the use of a compound of Formula (I),or a pharmaceutically acceptable salt, or N-oxide thereof in thetreatment or prevention of diseases or conditions that are estrogensensitive, estrogen receptor dependent or estrogen receptor mediated. Insome embodiments, the disease or condition is described herein.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are used to diminish,reduce, or eliminate the activity of estrogen receptors.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Estrogen receptor alpha (ER-α; NR3A1) and estrogen receptor beta (ER-β;NR3A2) are steroid hormone receptors, which are members of the largenuclear receptor superfamily. Nuclear receptors share a common modularstructure, which minimally includes a DNA binding domain (DBD) and aligand binding domain (LBD). Steroid hormone receptors are soluble,intracellular proteins that act as ligand-regulated transcriptionfactors. Vertebrates contain five closely related steroid hormonereceptors (estrogen receptor, androgen receptor, progesterone receptor,glucocorticoid receptor, mineralcorticoid receptor), which regulate awide spectrum of reproductive, metabolic and developmental activities.The activities of ER are controlled by the binding of endogenousestrogens, including 17β-estradiol and estrones.

The ER-α gene is located on 6q25.1 and encodes a 595 AA protein. TheER-β gene resides on chromosome 14q23.3 and produces a 530 AA protein.However, due to alternative splicing and translation start sites, eachof these genes can give rise to multiple isoforms. In addition to theDNA binding domain (called C domain) and ligand binding domain (Edomain) these receptors contain an N-terminal (A/B) domain, a hinge (D)domain that links the C and E domains, and a C-terminal extension (Fdomain) (Gronemeyer and Laudet; Protein Profile 2: 1173-1308, 1995).While the C and E domains of ER-α and ER-β are quite conserved (95% and55% amino acid identity, respectively), conservation of the A/B, D and Fdomains is poor (below 30% amino acid identity). Both receptors areinvolved in the regulation and development of the female reproductivetract but also play various roles in the central nervous system,cardiovascular systems and bone metabolism.

The ligand binding pocket of steroid hormone receptors is deeply buriedwithin the ligand binding domain. Upon binding, the ligand becomes partof the hydrophobic core of this domain. Consequently most steroidhormone receptors are instable in the absence of hormone and requireassistance from chaperones, such as Hsp90, in order to maintainhormone-binding competency. The interaction with Hsp90 also controlsnuclear translocation of these receptors. Ligand-binding stabilizes thereceptor and initiates sequential conformational changes that releasethe chaperones, alter the interactions between the various receptordomains and remodel protein interaction surfaces that allow thesereceptors to translocate into the nucleus, bind DNA and engage ininteractions with chromatin remodeling complexes and the transcriptionalmachinery. Although ER can interact with Hsp90, this interaction is notrequired for hormone binding and, dependent on the cellular context,apo-ER can be both cytoplasmic and nuclear. Biophysical studiesindicated that DNA binding rather than ligand binding contributes to thestability of the receptor (Greenfield et al., Biochemistry 40:6646-6652, 2001).

ER can interact with DNA either directly by binding to a specific DNAsequence motif called estrogen response element (ERE) (classicalpathway), or indirectly via protein-protein interactions (nonclassicalpathway) (Welboren et al., Endocrine-Related Cancer 16: 1073-1089,2009). In the nonclassical pathway, ER has been shown to tether to othertranscription factors including SP-1, AP-1 and NF-κB. These interactionsappear to play critical roles in the ability of ER to regulate cellproliferation and differentiation.

Both types of ER DNA interactions can result in gene activation orrepression dependent on the transcriptional coregulators that arerecruited by the respective ER-ERE complex (Klinge, Steroid 65: 227-251,2000). The recruitment of coregulators is primarily mediated by twoprotein interaction surfaces, the AF2 and AF1. AF2 is located in the ERE-domain and its conformation is directly regulated by the ligand(Brzozowski et al., Nature 389: 753-758, 1997). Full agonists appear topromote the recruitment of co-activators, whereas weak agonists andantagonists facilitate the binding of co-repressors. The regulation ofprotein with the AF1 is less well understood but can be controlled byserine phosphorylation (Ward and Weigel, Biofactors 35: 528-536, 2009).One of the involved phosphorylation sites (S118) appears to control thetranscriptional activity of ER in the presence of antagonists such astamoxifen, which plays an important role in the treatment of breastcancer. While full agonists appear to arrest ER in certain conformation,weak agonists tend to maintain ER in equilibrium between differentconformations, allowing cell-dependent differences in co-regulatorrepertoires to modulate the activity of ER in a cell-dependent manner(Tamrazi et al., Mol. Endocrinol. 17: 2593-2602, 2003). Interactions ofER with DNA are dynamic and include, but are not limited to, thedegradation of ER by the proteasome (Reid et al., Mol Cell 11: 695-707,2003). The degradation of ER with ligands provides an attractivetreatment strategy for disease or conditions that estrogen-sensitiveand/or resistant to available anti-hormonal treatments.

ER signaling is crucial for the development and maintenance of femalereproductive organs including breasts, ovulation and thickening of theendometrium. ER signaling also has a role in bone mass, lipidmetabolism, cancers, etc. About 70% of breast cancers express ER-α (ER-αpositive) and are dependent on estrogens for growth and survival. Othercancers also are thought to be dependent on ER-α signaling for growthand survival, such as for example ovarian and endometrial cancers. TheER-α antagonist tamoxifen has been used to treat early and advancedER-αpositive breast cancer in both pre- and post-menopausal women.Fulvestrant (Faslodex™) a steroid-based ER antagonist is used to treatbreast cancer in women which has have progressed despite therapy withtamoxifen. Steroidal and non-steroidal aromatase inhibitors are alsoused to treat cancers in humans. In some embodiments, the steroidal andnon-steroidal aromatase inhibitors block the production of estrogen fromandrostenedione and testosterone in post-menopausal women, therebyblocking ER dependent growth in the cancers. In addition to theseanti-hormonal agents, progressive ER positive breast cancer is treatedin some cases with a variety of other chemotherapeutics, such as forexample, the anthracylines, platins, taxanes. In some cases, ER positivebreast cancers that harbor genetic amplication of the ERB-B/HER2tyrosine kinase receptor are treated with the monoclonal antibodytrastuzumab (Herceptin™) or the small molecule pan-ERB-B inhibitorlapatinib. Despite this battery of anti-hormonal, chemotherapeutic andsmall-molecule and antibody-based targeted therapies, many women withER-αpositive breast develop progressive metastatic disease and are inneed of new therapies. Importantly, the majority of ER positive tumorsthat progress on existing anti-hormonal, as well as and other therapies,are thought to remain dependent on ER-α for growth and survival. Thus,there is a need for new ER-α targeting agents that have activity in thesetting of metastatic disease and acquired resistance.

In one aspect, described herein are compounds that are selectiveestrogen receptor modulators (SERMs). In specific embodiments, the SERMsdescribed herein are selective estrogen receptor degraders (SERDs). Insome embodiments, in cell-based assays the compounds described hereinresult in a reduction in steady state ER-αlevels (i.e. ER degradation)and are useful in the treatment of estrogen sensitive diseases orconditions and/or diseases or conditions that have developed resistantto anti-hormonal therapies. In some embodiments, compounds disclosedherein minimize levels of the estrogen receptor in the nucleus.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agent agentsthat modulate other critical pathways in breast cancer, including butnot limited to those that target IGF1R, EGFR, erB-B2 and 3 thePI3K/AKT/mTOR axis, HSP90, PARP or histone deacetylases.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agent used totreat breast cancer, including but not limited to aromatase inhibitors,anthracylines, platins, nitrogen mustard alkylating agents, taxanes.Illustrative agent used to treat breast cancer, include, but are notlimited to, paclitaxel, anastrozole, exemestane, cyclophosphamide,epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab,pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene,vinorelbine, capecitabine, ixabepilone, as well as others describedherein.

ER-related diseases or conditions (for which the agents disclosed hereinare therapeutically relevant) include ER-αdysfunction is also associatedwith cancer (bone cancer, breast cancer, colorectal cancer, endometrialcancer, prostate cancer, ovarian and uterine cancer), leiomyoma (uterineleiomyoma), central nervous system (CNS) defects (alcoholism, migraine),cardiovascular system defects (aortic aneurysm, susceptibility tomyocardial infarction, aortic valve sclerosis, cardiovascular disease,coronary artery disease, hypertension), hematological system defects(deep vein thrombosis), immune and inflammation diseases (Graves'Disease, arthritis, multiple sclerosis, cirrhosis), susceptibility toinfection (hepatitis B, chronic liver disease), metabolic defects (bonedensity, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia,osteoporosis), neurological defects (Alzheimer's disease, Parkinson'sdisease, migraine, vertigo), psychiatric defects (anorexia nervosa,attention deficit hyperactivity disorder (ADHD), dementia, majordepressive disorder, psychosis) and reproductive defects (age ofmenarche, endometriosis, infertility.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal. In some embodiments, the cancer is breast cancer, ovariancancer, endometrial cancer, prostate cancer, uterine cancer, cervicalcancer or lung cancer. In some embodiments, the cancer is breast cancer.In some embodiments, the cancer is a hormone dependent cancer. In someembodiments, the cancer is an estrogen receptor dependent cancer. Insome embodiments, the cancer is an estrogen-sensitive cancer. In someembodiments, the cancer is resistant to anti-hormonal treatment. In someembodiments, the cancer is an estrogen-sensitive cancer or an estrogenreceptor dependent cancer that is resistant to anti-hormonal treatment.In some embodiments, anti-hormonal treatment includes treatment with atleast one agent selected from tamoxifen, fulvestrant, steroidalaromatase inhibitors, and non-steroidal aromatase inhibitors-resistant.

In some embodiments, compounds disclosed herein are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In some embodiments, compounds disclosed herein are used to treat ahormonal dependent benign or malignant disease of the breast orreproductive tract in a mammal. In some embodiments, the benign ormalignant disease is breast cancer.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal, wherein the mammal is chemotherapy-naïve.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal, wherein the mammal is being treated for cancer with atleast one anti-cancer agent. In one embodiment, the cancer is a hormonerefractory cancer.

In some embodiments, compounds disclosed herein are used in thetreatment of endometriosis in a mammal.

In some embodiments, compounds disclosed herein are used in thetreatment of leiomyoma in a mammal. In some embodiments, the leiomyomais an uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma orsmall bowel leiomyoma. In some embodiments, compounds disclosed hereinare used in the treatment of fibroids in a mammal (e.g. uterinefibroids).

Compounds

Compounds of Formula (I), including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are estrogen receptor modulators. In specific embodiments, thecompounds described herein are estrogen receptor degraders. In specificembodiments, the compounds described herein are estrogen receptorantagonists. In specific embodiments, the compounds described herein areestrogen receptor degraders and estrogen receptor antagonists withminimal or no estrogen receptor agonist activity.

In some embodiments, compounds disclosed herein are estrogen receptordegraders and estrogen receptor antagonists that exhibit minimal or noestrogen receptor agonism; and/or anti-proliferative activity againstbreast cancer, ovarian cancer, endometrial cancer, cervical cancer celllines; and/or maximal anti-proliferative efficacy against breast cancer,ovarian cancer, endometrial cancer, cervical cell lines in-vitro; and/orminimal agonism in the human endometrial (Ishikawa) cell line; and/or noagonism in the human endometrial (Ishikawa) cell line; and/or minimal orno agonism in the immature rat uterine assay in-vivo; and/or inverseagonism in the immature rat uterine assay in-vivo; and/or anti-tumoractivity in breast cancer, ovarian cancer, endometrial cancer, cervicalcancer cell lines in xenograft assays in-vivo or other rodent models ofthese cancers.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt, or N-oxide thereof:

-   -   wherein,    -   Z is —OH or —OR¹⁰;    -   R² is C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄deuteroalkyl,        C₃-C₆cycloalkyl, or —C₁-C₄alkylene-W;        -   W is hydroxy, halogen, CN, C₁-C₄alkyl, C₁-C₄haloalkyl,            C₁-C₄alkoxy, C₁-C₄haloalkoxy, or C₃-C₆cycloalkyl;    -   each R³ is independently halogen, C₁-C₄alkyl, or        C₁-C₄-fluoroalkyl;    -   each R⁴ is independently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰,        C₁-C₄alkyl, C₁-C₄-fluoroalkyl, or C₁-C₄heteroalkyl;    -   each R⁵ is independently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰,        C₁-C₄alkyl, C₁-C₄-fluoroalkyl, or C₁-C₄heteroalkyl;    -   R⁶ is H, C₁-C₄alkyl, or halogen; R⁷ is H, C₁-C₄alkyl, or        halogen;    -   R⁹ is H, C₁-C₆alkyl, C₁-C₆-fluoroalkyl, or C₃-C₆cycloalkyl;    -   R¹⁰ is C₁-C₆alkyl;    -   m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2.

For any and all of the embodiments, substituents are selected from amongfrom a subset of the listed alternatives. For example, in someembodiments, Z is —OH. In some embodiments, Z is −OR¹⁰. In someembodiments, Z is —OH, —OCH₃, or —OCH₂CH₃.

In some embodiments, R⁶ is H, —CH₃, F, or Cl. In some embodiments, R⁶ isH.

In some embodiments, R⁷ is H, —CH₃, F, or Cl. In some embodiments, R⁷ isH.

In some embodiments, R⁹ is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl. In someembodiments, R⁹ is H or C₁-C₆alkyl. In some embodiments, R⁹ is H.

It is understood that R³ may be present on any open position of theindazole ring system. In some embodiments, each R³ is independentlyhalogen, C₁-C₄alkyl, or C₁-C₄-fluoroalkyl. In some embodiments,

each R³ is independently F, Cl, or —CH₃.

In some embodiments, each R⁴ is independently halogen, —CN, —OH, —OR⁹,—S(═O)₂R¹⁰, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄heteroalkyl,C₁-C₄-fluoroalkoxy, or C₁-C₄alkoxy. In some embodiments,

each R⁴ is independently halogen, —CN, —OH, —S(═O)₂CH₃, —S(═O)₂CH₂CH₃,—CH₃, —CH₂CH₃, —CF₃, —CH₂OH, —OCF₃, —OCH₃, or —OCH₂CH₃. In someembodiments, each R⁴ is independently F, Cl, —CN, —OH, —CH₃, —CH₂CH₃,—CF₃, —CH₂OH, —OCF₃, —OCH₃, or —OCH₂CH₃. In some embodiments, each R⁴ isindependently F or Cl.

In some embodiments, each R⁵ is independently halogen, C₁-C₄alkyl, orC₁-C₄-fluoroalkyl. In some embodiments, each R⁵ is independently F, Cl,or —CH₃.

In some embodiments, m is 0 or 1. In some embodiments, m is 0. In someembodiments, m is 1.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. Insome embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, p is 0 or 1. In some embodiments, p is 0. In someembodiments, p is 1.

In some embodiments, m is 0; and p is 0.

In some embodiments, Z is —OH; R⁶ is H, —CH₃, F, or Cl; R⁷ is H, —CH₃,F, or Cl; each R³ is independently halogen, C₁-C₄alkyl, orC₁-C₄-fluoroalkyl; each R⁴ is independently halogen, —CN, —OH, —OR⁹,—S(═O)₂R¹⁰, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄heteroalkyl,C₁-C₄-fluoroalkoxy, or C₁-C₄alkoxy; each R⁵ is independently halogen,C₁-C₄alkyl, or C₁-C₄-fluoroalkyl; m is 0 or 1; n is 0, 1, or 2; and p is0 or 1.

In some embodiments, R² is C₁-C₄alkyl, C₁-C₄-fluoroalkyl,C₁-C₄deuteroalkyl, C₃-C₆cycloalkyl, or —C₁-C₄alkylene-W; W is hydroxy,halogen, CN, C₁-C₄alkoxy, or C₃-C₆cycloalkyl. In some embodiments, R² isC₁-C₄alkyl, C₁-C₄-fluoroalkyl, or C₁-C₄deuteroalkyl. In someembodiments, R² is C₁-C₄alkyl. In some embodiments, R² is —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃,—CH₂CF₃, —CD₃, —CH₂CD₃, —CD₂CD₃, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, —CH₂—W, or —CH₂CH₂—W; W is hydroxy, F, Cl, —CN, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl. In some embodiments, W is hydroxy, F, Cl, —CN,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In someembodiments, R² is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CD₃, —CH₂CD₃, —CD₂CD₃,—CH₂—W, or —CH₂CH₂—W. In some embodiments, R² is —CH₃, —CH₂CH₃, —CH₂F,—CHF₂, —CF₃, —CH₂CF₃, —CD₃, —CD₂CD₃, —CH₂CD₃, cyclopropyl or cyclobutyl.In some embodiments, R² is —CH₂CH₃, —CH₂CF₃, —CD₂CD₃, or —CH₂CD₃. Insome embodiments, R² is —CH₂CH₃, —CD₂CD₃, or —CH₂CD₃. In someembodiments, R² is —CH₂CH₃ or cyclobutyl. In some embodiments, R² is—CH₂CH₃.

In some embodiments, each R³ is independently F, Cl, or —CH₃; and m is 0or 1.

In some embodiments, Z is —OH; R⁶ is H; R⁷ is H; m is 0; n is 0, 1, or2; and p is 0.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II), or a pharmaceutically acceptable salt, or N-oxide thereof:

In some embodiments, each R³ is independently F, Cl, or —CH₃; each R⁴ isindependently halogen, —CN, —OH, —S(═O)₂CH₃, —S(═O)₂CH₂CH₃, —CH₃,—CH₂CH₃, —CF₃, —CH₂OH, —OCF₃, —OCH₃, or —OCH₂CH₃; each R⁵ isindependently F, Cl, or —CH₃; m is 0 or 1; n is 0, 1, or 2; and p is 0or 1.

In some embodiments, R² is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CD₃, —CD₂CD₃,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH₂—W, or —CH₂CH₂—W;W is hydroxy, F, Cl, —CN, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, W is hydroxy, F, Cl, —CN, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl; each R⁴ is independently F, Cl, —CN, —OH,—CH₃, —CF₃, —OCF₃, or —OCH₃; m is 0 or 1; n is 0, 1, or 2; and p is 0.

In some embodiments, R² is —CH₂CH₃ or cyclobutyl; each R⁴ isindependently F, Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CF₃, —CH₂OH, —OCF₃,—OCH₃, or —OCH₂CH₃; m is 0 or 1; n is 0, 1, or 2; and p is 0. In someembodiments, R² is —CH₂CH₃; each R⁴ is independently F, Cl, —CN, —OH,—CH₃, —CH₂CH₃, —CF₃, —CH₂OH, —OCF₃, —OCH₃, or —OCH₂CH₃; m is 0; n is 0,1, or 2; and p is 0.

In some embodiments, the compound of Formula (I) or Formula (II) has thefollowing structure, or a pharmaceutically acceptable salt thereof, orN-oxide thereof:

In some embodiments,

is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2,6-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 2-fluoro-3-chlorophenyl,2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl,2-fluoro-6-chlorophenyl, 2-chloro-3-fluorophenyl,2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl,2-chloro-6-fluorophenyl, 2-methyl-3-chlorophenyl,2-methyl-4-chlorophenyl, 2-methyl-5-chlorophenyl,2-methyl-6-chlorophenyl, 2-methyl-3-fluorophenyl,2-methyl-4-fluorophenyl, 2-methyl-5-fluorophenyl,2-methyl-6-fluorophenyl, 3-methyl-4-fluorophenyl,2-trifluoromethyl-3-chlorophenyl, 2-trifluoromethyl-4-chlorophenyl,2-trifluoromethyl-5-chlorophenyl, 2-trifluoromethyl-6-chlorophenyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl,2-methylsulfonylphenyl, 3-methylsulfonylphenyl, or4-methylsulfonylphenyl.

In some embodiments,

is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2,6-dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-fluoro-4-methoxyphenyl,2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl,2-fluoro-5-chlorophenyl, 2-fluoro-6-chlorophenyl,2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl,2-chloro-5-fluorophenyl, 2-chloro-6-fluorophenyl,2-methyl-3-chlorophenyl, 2-methyl-4-chlorophenyl,2-methyl-5-chlorophenyl, 2-methyl-6-chlorophenyl,2-methyl-3-fluorophenyl, 2-methyl-4-fluorophenyl,2-methyl-5-fluorophenyl, 2-methyl-6-fluorophenyl,3-methyl-4-fluorophenyl, 2-trifluoromethyl-3-chlorophenyl,2-trifluoromethyl-4-chlorophenyl, 2-trifluoromethyl-5-chlorophenyl, or2-trifluoromethyl-6-chlorophenyl.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, the compound of Formula (I), is a compoundpresented in Table 1, or a pharmaceutically acceptable salt, or N-oxidethereof:

TABLE 1 LCMS* Compound Name Structure [M + H]⁺ 1 (E)-Ethyl3-(4-((E)-1-(1H- indazol-5-yl)-2-phenylbut-1- en-1-yl)phenyl)acrylate

423 2 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

395 3 (E)-3-(4-((E)-2-(4- Fluorophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

413 4 (E)-3-(4-((E)-2-(4- Chlorophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

429 5 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(3-methoxyphenyl)but-1-en-1-yl)phenyl)acrylic acid

425 6 (E)-3-(4-((E)-2-(3- (Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

425 7 (E)-3-(4-((E)-2-(4- (Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

425 8 (E)-3-(4-((E)-2-(2- (Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

425 9 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(o-tolyl)but-1-en-1-yl)phenyl)acrylic acid

409 10 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(m-tolyl)but-1-en-1-yl)phenyl)acrylic acid

409 11 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(p-tolyl)but-1-en-1-yl)phenyl)acrylic acid

409 12 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(2-methoxyphenyl)but-1-en-1-yl)phenyl)acrylic acid

425 13 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(4-methoxyphenyl)but-1-en-1-yl)phenyl)acrylic acid

425 14 ((E)-3-(4-((E)-2-(2- Chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

429 15 (E)-3-(4-((E)-2-(3- Chlorophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

429 16 (E)-3-(4-((E)-2-(2- Fluorophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

413 17 (E)-3-(4-((E)-2-(3- Fluorophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

413 18 (E)-3-(4-((E)-2-(2- Ethylphenyl)-1-(1H-indazol-5- yl)but-1-en-1-yl)phenyl)acrylic acid

423 19 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(2-(trifluoromethyl)phenyl)but-1- en-1-yl)phenyl)acrylic acid

463 20 (E)-3-(4-((E)-4-Chloro-1-(1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

429 21 (E)-3-(4-((E)-2-(2- Cyanophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

420 22 (E)-3-(4-((E)-2-(2,4- Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

431 23 (E)-3-(4-((E)-2-(2-Chloro-3- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

447 24 (E)-3-(4-((E)-2-Cyclopropyl- 1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid

407 25 (E)-3-(4-((E)-2-(4-Fluoro-2- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

427 26 (E)-3-(4-((E)-2-(2,6- Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

431 27 (E)-3-(4-((E)-2-(2,6- Dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

463 28 (E)-3-(4-((E)-4,4,4-Trideutero- 1-(1H-indazol-5-yl)-2-phenylbut-1-en-1- yl)phenyl)acrylic acid

398 29 (E)-3-(4-((E)-2-(4-Fluoro-3- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

427 30 (E)-3-(4-((E)-2-(5-Fluoro-2- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

427 31 (E)-3-(4-((E)-2-(2,3- Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

431 32 (E)-3-(4-((E)-2-(2,5- Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

431 33 (E)-3-(4-((E)-2-(2-Chloro-5- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

447 34 (E)-3-(4-((E)-2-(2-Chloro-6- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1 yl)phenyl)acrylic acid

443 35 (E)-3-(4-((E)-1-(7-Chloro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

429 36 (E)-3-(4-((E)-1-(4-Methyl-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

409 37 (E)-3-(4-((E)-1-(7-Methyl-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

409 38 (E)-3-(4-((E)-1-(6-Methyl-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

409 39 (E)-3-(4-((E)-1-(3-Methyl-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

409 40 (E)-3-(4-((E)-1-(3-Chloro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

429 41 (E)-3-(4-((E)-2-(4-Chloro-2- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

443 42 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid

381 43 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylpent-1-en-1-yl)phenyl)acrylic acid

409 44 (E)-3-(4-((E)-2-(3- Cyanophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

420 45 (E)-3-(4-((E)-2-(4- Cyanophenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

420 46 (E)-3-(4-((E)-4-Hydroxy-1- (1H-indazol-5-yl)-2- phenylbut-1-en-1-yl)phenyl)acrylic acid

411 47 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-4-methoxy-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

425 48 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-3-methoxy-2-phenylprop-1-en-1-yl)phenyl)acrylic acid

411 49 (E)-3-(4-((E)-1-(4-Fluoro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

413 50 (E)-3-(4-((E)-1-(6-Chloro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

429 51 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-4-methyl-2-phenylpent-1-en-1-yl)phenyl)acrylic acid

423 52 (E)-3-(4-((E)-1-(4-Chloro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

429 53 (E)-3-(4-((E)-2-Cyclopentyl-1- (1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid

435 54 (E)-3-(4-((E)-2-Cyclohexyl-1- (1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid

449 55 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

409 56 (E)-3-(4-((E)-3-Cyclopropyl- 1-(1H-indazol-5-yl)-2-phenylprop-1-en-1- yl)phenyl)acrylic acid

421 57 (E)-3-(4-((E)-2-(2- Chlorophenyl)-2-cyclopropyl- 1-(1H-indazol-5-yl)vinyl)phenyl)acrylic acid

441 58 (E)-3-(4-((E)-1-(6-Fluoro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

413 59 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylhex-1-en-1-yl)phenyl)acrylic acid

423 60 (E)-3-(4-((E)-3-Cyclopentyl-1- (1H-indazol-5-yl)-2-phenylprop-1-en-1- yl)phenyl)acrylic acid

449 61 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

465 62 (E)-3-(4-((E)-1-(7-Fluoro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

413 63 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(1H-indazol-5-yl)-4-methylpent-1-en-1- yl)phenyl)acrylic acid

475 64 (E)-3-(4-((Z)-3,3-Difluoro-1- (1H-indazol-5-yl)-2-phenylprop-1-en-1- yl)phenyl)acrylic acid

417 65 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

465 66 (E)-3-(4-((E)-4-Fluoro-1-(1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

413 67 (E)-3-(4-((E)-4-Chloro-2-(2- chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

481 68 (E)-3-(4-((Z)-3,3,3-Trifluoro- 1-(1H-indazol-5-yl)-2-phenylprop-1-en-1- yl)phenyl)acrylic acid

not observed 69 (E)-3-(4-((E)-1-(4-Fluoro-1H-indazol-5-yl)-2-(4-fluoro-2- methylphenyl)but-1-en-1- yl)phenyl)acrylicacid

445 70 (E)-3-(4-((E)-2-(4-Chloro-2- methylphenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

461 71 (E)-3-(4-((E)-2-Cyclopropyl- 1-(4-fluoro-1H-indazol-5-yl)-2-(4-fluoro-2- methylphenyl)vinyl)phenyl)acrylic acid

457 72 (E)-3-(4-((E)-2-(4-Chloro-2- methylphenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5- yl)vinyl)phenyl)acrylic acid

473 73 (E)-3-(4-((E)-1-(4-Chloro-1H- indazol-5-yl)-2-(2-chloro-4-fluorophenyl)but-1-en-1- yl)phenyl)acrylic acid

481 74 (E)-3-(4-((Z)-2-(2-Chloro-4- fluorophenyl)-3,3-difluoro-1-(1H-indazol-5-yl)prop-1-en-1- yl)phenyl)acrylic acid

469 75 (E)-3-(4-((E)-2-Cyclopropyl- 1-(4-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid

425 76 (E)-3-(4-((E)-4-Chloro-1-(4- fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1- yl)phenyl)acrylic acid

447 77 (E)-3-(4-((E)-4-Chloro-2-(2- chloro-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1- en-1-yl)phenyl)acrylic acid

499 78 (E)-3-(4-((E)-4-Fluoro-2-(4- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

431 79 (E)-3-(4-((E)-4-Fluoro-1-(4- fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1- yl)phenyl)acrylic acid

431 80 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-5-methoxy-2-phenylpent-1-en-1-yl)phenyl)acrylic acid

439 81 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-6-methoxy-2-phenylhex-1-en-1-yl)phenyl)acrylic acid

453 82 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(1H-indazol-5-yl)-3-methylbut-1-en-1- yl)phenyl)acrylic acid

461 83 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(3-(trifluoromethoxy)phenyl)but- 1-en-1-yl)phenyl)acrylic acid

479 84 (E)-3-(4-((E)-2-Cyclobutyl-1- (1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid

421 85 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-2-cyclobutyl-1-(1H-indazol-5- yl)vinyl)phenyl)acrylic acid

473 86 (E)-3-(4-((E)-1-(3-Fluoro-1H- indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

413 87 (E)-3-(4-((E)-2-Cyclobutyl-1- (3-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid

439 88 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

465 89 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5- yl)vinyl)phenyl)acrylic acid

491 90 (E)-Ethyl 3-(4-((E)-2-(4- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylate

441 91 (E)-Ethyl 3-(4-((E)-1-(1H- Indazol-5-yl)-2-(2-methoxyphenyl)but-1-en-1- yl)phenyl)acrylate

453 92 (E)-Ethyl 3-(4-((E)-1-(1H- Indazol-5-yl)-2-(4-methoxyphenyl)but-1-en-1- yl)phenyl)acrylate

453 93 (E)-3-(4-((E)-2-(3- Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

411 94 (E)-3-(4-((E)-2-(2- Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

411 95 (E)-3-(4-((E)-2-(4- Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

411 96 (E)-3-(4-((E)-2-(3- Butoxyphenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

467 97 (E)-3-(4-((E)-2-(4- Butoxyphenyl)-1-(1H-indazol- 5-yl)but-1-en-1-yl)phenyl)acrylic acid

467 98 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(2-(methylsulfonyl)phenyl)but-1- en-1-yl)phenyl)acrylic acid

473 99 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)phenyl)-2-methylacrylic acid

409 100 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-3-methylphenyl)acrylic acid

409 101 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-2-methylphenyl)acrylic acid

409 102 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-2-chlorophenyl)acrylic acid

429 103 (Z)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)phenyl)-2-fluoroacrylic acid

413 104 (Z)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)phenyl)-2-chloroacrylic acid

429 105 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-3-fluorophenyl)acrylic acid

413 106 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-2-fluorophenyl)acrylic acid

413 107 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-2-(trifluoromethyl)phenyl)acrylic acid

463 108 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-3-methoxyphenyl)acrylic acid

425 109 (E)-3-(4-((Z)-1-(1H-Indazol-5- yl)-2-phenylbut-1-en-1-yl)-2-methoxyphenyl)acrylic acid

425 110 (E)-Ethyl 3-(4-((E)-2-(2- chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylate hydrochloride

475 111 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

447 112 (E)-Ethyl 3-(4-((E)-2-(2,4- dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylate

491 113 (E)-3-(4-((E)-2-(2,4- Dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

463 114 (E)-3-(4-((E)-2-(4-Chloro-2- (trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

497 115 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-2-cyclopropyl-1-(1H-indazol-5- yl)vinyl)phenyl)acrylic acid

459 116 (E)-3-(4-((E)-2-(4-Fluoro-2- (trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

481 117 (E)-3-(4-(1-(4-Fluoro-1H- indazol-5-yl)-2-(4-fluoro-2-(trifluoromethyl) phenyl)butyl)phenyl)acrylic acid

499 118 (E)-3-(4-((E)-2-(2,4- Dichlorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

481 119 (E)-3-(4-((E)-2-(4-Chloro-2- (trifluoromethyl)phenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1- en-1-yl)phenyl)acrylic acid

515 120 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-4-fluoro-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

465 121 (E)-3-(4-((E)-2-(2-Chloro-4- methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

459 122 (E)-3-(4-((E)-2-(2,4- Dichlorophenyl)-4-fluoro-1-(4-fluoro-1H-indazol-5-yl)but- 1-en-1-yl)phenyl)acrylic acid

499 123 (E)-3-(4-((E)-2-Cyclopropyl- 2-(2,4-dichlorophenyl)-1-(4-fluoro-1H-indazol-5- yl)vinyl)phenyl)acrylic acid

493 124 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5- yl)vinyl)phenyl)acrylic acid

477 125 (E)-3-(4-((E)-2-Cyclopropyl- 2-(2,4-dichlorophenyl)-1-(1H-indazol-5- yl)vinyl)phenyl)acrylic acid

475 126 (E)-3-(4-((E)-2-(4-Chloro-2- methylphenyl)-2-cyclopropyl-1-(1H-indazol-5- yl)vinyl)phenyl)acrylic acid

455 127 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(2-methyl-5-(methylsulfonyl)phenyl)but-1- en-1-yl)phenyl)acrylic acid

487 128 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(4-methoxy-2-methylphenyl)but-1-en-1- yl)phenyl)acrylic acid

439 129 (E)-3-(4-((E)-2-(2-Fluoro-4- methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

443 130 (E)-3-(4-((E)-2-(2-Chloro-5- methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

459 131 (E)-3-(4-((E)-2-(2-Fluoro-4- (methylsulfonyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

491 132 (E)-3-(4-((E)-2-(2,4- Dichlorophenyl)-3,3,4,4,4-pentadeutero-1-(1H-indazol-5- yl)but-1-en-1- yl)phenyl)acrylic acid

468 133 (E)-3-(4-((E)-1-(1H-Indazol-5- yl)-2-(3-(methylsulfonyl)phenyl)but-1- en-1-yl)phenyl)acrylic acid

473 134 (E)-3-(4-((E)-2-(2,4- Dichlorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

481 135 (E)-3-(4-((E)-2-(2-Chloro-3- methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

459 136 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-3,3,4,4,4-pentadeutero-1-(1H-indazol-5- yl)but-1-en-1- yl)phenyl)acrylic acid

452 137 (E)-3-(4-((E)-2-(4-Chloro-2- cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

454 138 (E)-3-(4-((E)-2-(2-Cyano-4- fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

438 139 (E)-3-(4-((E)-2-(2-Cyano-4- (trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

488 140 (E)-3-(4-((E)-2-(2-Chloro-4- cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

454 141 (E)-3-(4-((E)-2-(3-Cyano-2- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

434 142 (E)-3-(4-((E)-2-(4-Cyano-2- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

434 143 (E)-3-(4-((E)-2-(5-Cyano-2- methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

434 144 (E)-3-(4-((E)-2-(2-Cyano-4- methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

450 145 (E)-3-(4-((E)-2-(2- Chlorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1 yl)phenyl)acrylic acid

443 146 (E)-3-(4-((E)-2-Cyclobutyl-1- (1-methyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid

435 147 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1- yl)phenyl)acrylic acid

461 148 (E)-3-(4-((E)-2-(2-Chloro-4- fluorophenyl)-1-(1-(difluoromethyl)-1H-indazol- 5-yl)but-1-en-1- yl)phenyl)acrylic acid

497 *mass spectrometric data

Synthesis of Compounds

Compounds of Formula (I), described herein, are synthesized usingstandard synthetic techniques or using methods known in the art incombination with methods described herein. In addition, solvents,temperatures and other reaction conditions presented herein may vary.

The starting material used for the synthesis of the compounds of Formula(I) are either synthesized or obtained from commercial sources, such as,but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar,and the like. The compounds described herein, and other relatedcompounds having different substituents are synthesized using techniquesand materials described herein or otherwise known, including those foundin March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey andSundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS3^(rd) Ed., (Wiley 1999). General methods for the preparation ofcompounds is optionally modified by the use of appropriate reagents andconditions for the introduction of the various moieties found in theformulae as provided herein.

In some embodiments, exemplary compounds of Formula (I) are prepared asoutlined in the following Schemes.

Protection of the acidic proton bearing nitrogen of compounds ofstructure 1 with a protecting group provides compounds of Structure 2.In some embodiments, the protecting group is tetrahydro-2H-pyran (THP).In some embodiments, the conditions for nitrogen protection require3,4-dihydro-2H-pyran (DHP), an organic acid and a suitable solvent. Insome embodiments, the organic acid is pyridinium p-toluenesulfonate(PPTS) or p-toluenesulfonic acid (p-TSA or p-TsOH) and the suitablesolvent is dichloromethane. In some embodiments, the reaction isperformed at room temperature. Other conditions to protect the nitrogenof the starting material are known. A detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

Compounds of structure 2, where X is a halgen or other suitable leavinggroup, are reacted with a protected acetylene (e.g.,trimethylsilylacetylene) under Sonogashira reaction conditions toprovide compounds of Structure 3. In some embodiments, the Sonogashiracoupling reaction conditions include the use of a palladium catalyst anda copper halide salt. In some embodiments, the Sonogashira reactionconditions in the use of Pd(Ph₃P)₂Cl₂, CuI, and triethylamine. In oneembodiment, the reaction is performed at about 80° C. Other suitablereaction conditions are described in Rafael Chinchilla and Carmen Nájera(2007). Chem. Rev. 107 (3): 874-922.

The silyl protecting group of compounds of structure 3 is removed undersuitable reaction conditions to provide compounds of structure 4. Insome embodiments, the silyl protecting group is removed with potassiumcarbonate (K₂CO₃) in methanol. In other embodiments, the silylprotecting group is removed with tetrabutylammoniumfluoride (TBAF) intetrahydrofuran.

In some embodiments, acetylenes of Structure 4 are reacted with R²—Xunder basic condition to prepare compounds of Structure 5. In theseinstances, R² is C₁-C₆alkyl or C₁-C₆-fluoroalkyl or C₁-C₄alkoxy orC₁-C₄-fluoroalkoxy or C₃-C₆cycloalkyl, or the like, and X is a suitableleaving group. In some embodiments, R² moieties are installed by othersuitable conditions.

In some embodiments, compounds of structure 2 are coupled with analkynyl-trimethylsilane or a terminal-alkyne under Sonogashira reactionconditions to provide compounds of structure 5. In some embodiments, thecoupling of an alkynyl-trimethylsilane with compounds of structure 2includes the use of a base (e.g. cesium carbonate), a palladium catalyst(e.g. Pd(OAc)₂, dppf) and a copper halide salt (e.g. CuI) in a suitablesolvent (e.g. dimethylacetamide), at elevated temperatures (e.g. about80-90° C.). In some embodiments, the coupling of a terminal-alkyne withcompounds of structure 2 includes the use of Pd(PPh₃)₂Cl₂), CuI, andtriethylamine, with the reaction performed with at elevated temperatures(e.g. about 80-120° C.).

Compounds of Structures 5, 6 and 7 are then coupled together undersuitable reaction conditions to afford compounds of Structure 8. In someembodiments, the suitable reaction conditions include the use oforganometallic reagent(s). In some embodiments, the suitable reactionconditions include the use of a palladium catalyst. In some embodiments,the suitable reaction conditions include the use of Pd(PhCN)₂Cl₂, K₂CO₃in dimethylformamide/water. Other suitable reaction conditions includethose described in Chengxiang Zhou and Richard C. Larock, Journal ofOrganic Chemistry, 2005, 70, 3765-3777; Chengxiang Zhou, Daniel E.Emrich, and Richard C. Larock Organic Letters 2003, 1579-1582; TsutomuKonno, Ken-ichi Taku, Takashi Ishihara, Journal of Fluorine Chemistry127 (2006) 966-972.

The protecting group of compounds of structure 8 is then removed undersuitable reaction conditions to provide compounds of structure 9. Insome embodiments, the suitable reaction conditions include the use of anacid. In some embodiments, the suitable reaction conditions include theuse of hydrochloric acid, ethanol, with the reaction performed at about70° C.

Hydrolysis of the ester group of compounds of structure 9 providescarboxylic acid compounds of structure 10. In some embodiments, thehydrolysis reaction includes the use of lithium hydroxide in a mixtureof tetrahydrofuran and ethanol. Other hydrolysis reaction conditions areknown.

In some embodiments, compounds disclosed herein are prepared as outlinedin Scheme 3.

In some embodiments, compounds of structure 5 are reacted with phenylhalides of structure 6 and boronic acids of structure 11 under suitablereaction conditions to provide compounds of structure 12. In someembodiments, the suitable reaction conditions include the use oforganometallic reagent(s). In some embodiments, the suitableorganometallic reagent is a palladium catalyst. The aldehyde ofcompounds of structure 12 is then transformed to an alkene undersuitable reaction conditions to provide compounds of structure 8.Suitable reaction conditions include a Horner-Wadsworth-Emmonsolefination reaction or a Wittig olefination reaction conditions.

Alternatively, compounds of structure 5 are reacted with a borylatingagent in the presence of a suitable catalyst to provide compounds ofstructure 13. In some embodiments, the suitable catalyst is anorganometallic reagent such as a platinum catalyst. In some embodiments,the amount of catalyst impacts the rate of the reaction, but generally,not the yield or purity. In some embodiments, the solvent has a smallimpact on the rate of the reaction, but generally, not the yield orpurity. In some embodiments, the temperature has a significant impact onthe rate of the reaction, but generally, not the yield or purity. ASuzuki cross-coupling is then performed with compounds of structure 13and phenyl halides of structure 14 to provide compounds of structure 15.In some embodiments, 2 or 3 equivalents of base (e.g. Cs₂CO₃) is used inthe Suzuki cross-coupling. In some embodiments, 1.3 equivalents of base(e.g. Cs₂CO₃) is used in the Suzuki cross-coupling. In some embodiments,the solvent has a significant impact on the rate and regioselectivity ofthis reaction. In some embodiments, dioxane, DME, or 2-MeTHF is used. Insome embodiments, water content has a significant impact on the rate andregioselectivity of this the Suzuki cross-coupling. A subsequent Suzukicross-coupling is then performed between compounds of structure 15 andphenyl halides of structure 16 to provide compounds of structure 12.

A detailed description of techniques applicable to the creation ofprotecting groups and their removal are described in Greene and Wuts,Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, NewYork, N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, NewYork, N.Y., 1994, which are incorporated herein by reference for suchdisclosure.

Further Forms of Compounds

In instances where the compound of Formula (I) possesses one or morestereocenters, each stereocenter exists independently in either the R orS configuration. The compounds presented herein include alldiastereomeric, enantiomeric, atropisomers, and epimeric forms as wellas the appropriate mixtures thereof. The compounds and methods providedherein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof.

Stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns and/or use of optically active resolvingagents. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981.

In certain embodiments, the compounds presented herein are present asatropisomers. Atropisomers refer to stereoisomers resulting fromhindered rotation about single bonds where the steric strain barrier torotation allows for the isolation of conformers. Atropisomers displayaxial chirality. Separation of atropisomers is possible. In someembodiments, separation of atropisomers is possible by chiral resolutionmethods such as selective crystallization. Atropisomers are optionallycharacterized by NMR or other suitable characterization means.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug or theyare bioavailable by oral administration or they have improved solubilityin pharmaceutical compositions over the parent drug. In someembodiments, the design of a prodrug increases the effective watersolubility. An example, without limitation, of a prodrug is a compounddescribed herein, which is administered as an ester (the “prodrug”) butthen is metabolically hydrolyzed to provide the active entity. Incertain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound.

In some embodiments, sites on the aromatic ring portion of compounds ofFormula (I) are susceptible to various metabolic reactions.Incorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, deuterium or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

“Pharmaceutically acceptable,” as used herein, refers to a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material is administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, pharmaceuticallyacceptable salts are obtained by reacting a compound of Formula (I) withan acid. Pharmaceutically acceptable salts are also obtained by reactinga compound of Formula (I) with a base to form a salt.

Compounds described herein are optionally formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein coordinate with an organic base,such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as lysine salts, sodium saltsand other suitable amino acid salts. In some embodiments, the compoundsprovided herein are prepared as a sodium salt. In some embodiments, thecompounds provided herein are prepared as an N-methylglucamine salt. Insome embodiments, the compounds provided herein are prepared as ahydrochloride salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structureof Formula (I), as well as active metabolites of these compounds havingthe same type of activity.

Certain Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. In this application, the use of “or” or “and”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is saturated or unsaturated. The alkyl moiety, whether saturatedor unsaturated, is branched or straight chain. In one aspect the alkylis selected from the group consisting of methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkylgroups include, but are in no way limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl,neopentyl, hexyl, allyl, vinyl, acetylene, but-2-enyl, but-3-enyl, andthe like.

“Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atomsof an alkyl are replaced with deuterium.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl or cyclohexenyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an antagonist. In some embodiments, amodulator is a degrader.

“Selective estrogen receptor modulator” or “SERM” as used herein, refersto a molecule that differentially modulates the activity of estrogenreceptors in different tissues. For example, in some embodiments, a SERMdisplays ER antagonist activity in some tissues and ER agonist activityin other tissues. In some embodiments, a SERM displays ER antagonistactivity in some tissues and minimal or no ER agonist activity in othertissues. In some embodiments, a SERM displays ER antagonist activity inbreast tissues, ovarian tissues, endometrial tissues, and/or cervicaltissues but minimal or no ER agonist activity in uterine tissues.

The term “antagonist” as used herein, refers to a small-molecule agentthat binds to a nuclear hormone receptor and subsequently decreases theagonist induced transcriptional activity of the nuclear hormonereceptor.

The term “agonist” as used herein, refers to a small-molecule agent thatbinds to a nuclear hormone receptor and subsequently increases nuclearhormone receptor transcriptional activity in the absence of a knownagonist.

The term “inverse agonist” as used herein, refers to a small-moleculeagent that binds to a nuclear hormone receptor and subsequentlydecreases the basal level of nuclear hormone receptor transcriptionalactivity that is present in the absence of a known agonist.

The term “degrader” as used herein, refers to a small molecule agentthat binds to a nuclear hormone receptor and subsequently lowers thesteady state protein levels of said receptor. In some embodiments, adegrader as described herein lowers steady state estrogen receptorlevels by at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%.

The term “selective estrogen receptor degrader” or “SERD” as usedherein, refers to a small molecule agent that preferentially binds toestrogen receptors versus other receptors and subsequently lowers thesteady state estrogen receptor levels.

The term “ER-dependent”, as used herein, refers to diseases orconditions that would not occur, or would not occur to the same extent,in the absence of estrogen receptors.

The term “ER-mediated”, as used herein, refers to diseases or conditionsthat occur in the absence of estrogen receptors but can occur in thepresence of estrogen receptors.

The term “ER-sensitive”, as used herein, refers to diseases orconditions that would not occur, or would not occur to the same extent,in the absence of estrogens.

The term “cancer” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, uterus, lymphatic tissue (lymphoma),ovary, pancreas or other endocrine organ (thyroid), prostate, skin(melanoma or basal cell cancer) or hematological tumors (such as theleukemias and lymphomas) at any stage of the disease with or withoutmetastases.

Additional non-limiting examples of cancers include, acute lymphoblasticleukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer,appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer(osteosarcoma and malignant fibrous histiocytoma), brain stem glioma,brain tumors, brain and spinal cord tumors, breast cancer, bronchialtumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia,chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, non-small cell lung cancer, small cell lungcancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma,non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,non-small cell lung cancer, oral cancer, oropharyngeal cancer,osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, papillomatosis,parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymaltumors of intermediate differentiation, pineoblastoma and supratentorialprimitive neuroectodermal tumors, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula (I), and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to humans, chimpanzees, apes, monkeys,cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats, mice,guinea pigs, and the like. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal,buccal, topical, rectal, aerosol, ophthalmic, pulmonary, transmucosal,transdermal, vaginal, otic, nasal, and topical administration. Inaddition, by way of example only, parenteral delivery includesintramuscular, subcutaneous, intravenous, intramedullary injections, aswell as intrathecal, direct intraventricular, intraperitoneal,intralymphatic, and intranasal injections. In certain embodiments, acompound as described herein is administered in a systemic manner. Incertain other embodiments, a compound as described herein isadministered in a local rather than systemic manner.

Pharmaceutical Compositions/Formulations

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), with other chemical components (i.e.pharmaceutically acceptable inactive ingredients), such as carriers,excipients, binders, filling agents, suspending agents, flavoringagents, sweetening agents, disintegrating agents, dispersing agents,surfactants, lubricants, colorants, diluents, solubilizers, moisteningagents, plasticizers, stabilizers, penetration enhancers, wettingagents, anti-foaming agents, antioxidants, preservatives, or one or morecombination thereof. The pharmaceutical composition facilitatesadministration of the compound to a mammal.

The pharmaceutical compositions will include at least one compound ofFormula (I), or a pharmaceutically acceptable salt thereof, as an activeingredient in free-acid or free-base form, or in a pharmaceuticallyacceptable salt form. In addition, the methods and pharmaceuticalcompositions described herein include the use of N-oxides (ifappropriate), crystalline forms, amorphous phases, as well as activemetabolites of these compounds having the same type of activity. In someembodiments, compounds described herein exist in unsolvated form or insolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like.

The pharmaceutical formulations described herein include, but are notlimited to, aqueous liquid dispersions, self-emulsifying dispersions,solid solutions, liposomal dispersions, aerosols, solid dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, delayedrelease formulations, extended release formulations, enteric coatedformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate and controlled release formulations.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered systemically.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered orally. All formulations fororal administration are in dosages suitable for such administration. Insome embodiments, the solid dosage forms disclosed herein are in theform of a tablet, a pill, a powder, a capsule, solid dispersion, solidsolution, bioerodible dosage form, controlled release formulations,pulsatile release dosage forms, multiparticulate dosage forms, beads,pellets, granules. In other embodiments, the pharmaceutical formulationis in the form of a powder. In still other embodiments, thepharmaceutical formulation is in the form of a tablet. In still otherembodiments, the pharmaceutical formulation is in the form of asuspension tablet, a fast-melt tablet, a bite-disintegration tablet, arapid-disintegration tablet, an effervescent tablet, or a caplet. Inother embodiments, pharmaceutical formulation is in the form of acapsule.

In some embodiments, the pharmaceutical solid oral dosage forms areformulated to provide a controlled release of the active compound.Controlled release profiles include, for example, sustained release,prolonged release, pulsatile release, and delayed release profiles.

In one aspect, liquid formulation dosage forms for oral administrationare in the form of aqueous suspensions selected from the groupincluding, but not limited to, pharmaceutically acceptable aqueous oraldispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g.,Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.754-757 (2002).

For buccal or sublingual administration, the compositions optionallytake the form of tablets, lozenges, or gels formulated in a conventionalmanner.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is formulated into a pharmaceutical compositionsuitable for intramuscular, subcutaneous, or intravenous injection.Parenteral injections involve either bolus injection and/or continuousinfusion.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered intravenously. In someembodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered subcutaneously.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered topically. In such embodiments,the compound of Formula (I), or a pharmaceutically acceptable saltthereof, is formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages,balms, creams or ointments. In some embodiments, the compound of Formula(I), or a pharmaceutically acceptable salt thereof, is administeredtopically to the skin of mammal. In some embodiments, the compound ofFormula (I), is prepared as a transdermal dosage form.

In another aspect is the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating a disease, disorder or conditions in which theactivity of estrogen receptors contributes to the pathology and/orsymptoms of the disease or condition. In one aspect, the disease orcondition is any of the diseases or conditions specified herein.

Methods of Dosing and Treatment Regimens

In one embodiment, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom a reduction of estrogen receptor activity. Methods for treating anyof the diseases or conditions described herein in a mammal in need ofsuch treatment, involves administration of pharmaceutical compositionsthat include at least one compound of Formula (I), or a pharmaceuticallyacceptable salt, N-oxide, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said mammal.

Therapeutically effective amounts depend on the severity and course ofthe disease or condition, previous therapy, the patient's health status,weight, and response to the drugs, and the judgment of the treatingphysician. Therapeutically effective amounts are optionally determinedby methods including, but not limited to, a dose escalation clinicaltrial.

In any of the method of treatments described herein, the effectiveamount of the compound of Formula (I) is: (a) systemically administeredto the mammal; and/or (b) administered orally to the mammal; and/or (c)intravenously administered to the mammal; and/or (d) administered byinjection to the mammal; and/or (e) administered topically to themammal; and/or (f) administered non-systemically or locally to themammal.

In some situations the methods of treatment comprise singleadministration of the effective amount of the compound, includingfurther embodiments in which (i) the compound is administered once; (ii)the compound is administered to the mammal multiple times over the spanof one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the compound is administered chronically,that is, for an extended period of time.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”).

In some embodiments, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously or atappropriate intervals, for example as two, three, four or more sub-dosesper day. In one embodiment, the daily dosages appropriate for thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,described herein are from about 0.01 to about 50 mg/kg per body weight.

Combination Therapy

In certain instances, it is appropriate to administer at least onecompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with one or more other therapeutic agents. In certainembodiments, the pharmaceutical composition further comprises one ormore anti-cancer agents.

In one specific embodiment, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is co-administered with asecond therapeutic agent, wherein the compound of Formula (I), or apharmaceutically acceptable salt thereof, and the second therapeuticagent modulate different aspects of the disease, disorder or conditionbeing treated, thereby providing a greater overall benefit thanadministration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is the additiveeffect of the two therapeutic agents or the patient may experience asynergistic benefit.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

In some embodiments, methods for treatment of estrogenreceptor-dependent or estrogen receptor-mediated conditions or diseases,such as proliferative disorders, including cancer, comprisesadministration to a mammal a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with at leastone additional therapeutic agent.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in combination with hormone blocking therapy,chemotherapy, radiation therapy, monoclonal antibodies, or combinationsthereof.

In some embodiments, the at least one additional therapeutic agent foruse in combination with a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, include one or more of the following:abiraterone; abarelix; adriamycin; actinomycin; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; alemtuzumab;allopurinol; alitretinoin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; aminolevulinic acid; amifostine; amsacrine;anastrozole; anthramycin; aprepitant; arsenic trioxide; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; bendamustinehydrochloride; benzodepa; bevacizumab; bexarotene; bicalutamide;bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin;bleomycin sulfate; bortezomib; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; capecitabine;cedefingol; cetuximab; chlorambucil; cirolemycin; cisplatin; cladribine;clofarabine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; dasatinib; daunorubicin hydrochloride; dactinomycin;darbepoetin alfa; decitabine; degarelix; denileukin diftitox;dexormaplatin; dexrazoxane hydrochloride; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; eltrombopagolamine; enloplatin; enpromate; epipropidine; epirubicin hydrochloride;epoetin alfa; erbulozole; erlotinib hydrochloride; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; everolimus; exemestane;fadrozole hydrochloride; fazarabine; fenretinide; filgrastim;floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine;fosquidone; fostriecin sodium; fulvestrant; gefitinib; gemcitabine;gemcitabine hydrochloride; gemcitabine-cisplatin; gemtuzumab ozogamicin;goserelin acetate; histrelin acetate; hydroxyurea; idarubicinhydrochloride; ifosfamide; iimofosine; ibritumomab tiuxetan; idarubicin;ifosfamide; imatinib mesylate; imiquimod; interleukin I1 (includingrecombinant interleukin I1, or r1L2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a;interferon gamma-1b; iproplatin; irinotecan hydrochloride; ixabepilone;lanreotide acetate; lapatinib; lenalidomide; letrozole; leuprolideacetate; leucovorin calcium; leuprolide acetate; levamisole; liposomalcytarabine; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium;methoxsalen; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;mitogillin; mitomalcin; mitomycin C; mitosper; mitotane; mitoxantronehydrochloride; mycophenolic acid; nandrolone phenpropionate; nelarabine;nilotinib; nocodazoie; nofetumomab; nogalamycin; ofatumumab; oprelvekin;ormaplatin; oxaliplatin; oxisuran; paclitaxel; palifermin; palonosetronhydrochloride; pamidronate; pegfilgrastim; pemetrexed disodium;pentostatin; panitumumab; pazopanib hydrochloride; pemetrexed disodium;plerixafor; pralatrexate; pegaspargase; peliomycin; pentamustine;peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;prednimustine; procarbazine hydrochloride; puromycin; puromycinhydrochloride; pyrazofurin; quinacrine; raloxifene hydrochloride;rasburicase; recombinant HPV bivalent vaccine; recombinant HPVquadrivalent vaccine; riboprine; rogletimide; rituximab; romidepsin;romiplostim; safingol; safingol hydrochloride; sargramostim; semustine;simtrazene; sipuleucel-T; sorafenib; sparfosate sodium; sparsomycin;spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin;streptozocin; sulofenur; sunitinib malate; talisomycin; tamoxifencitrate; tecogalan sodium; tegafur; teloxantrone hydrochloride;temozolomide; temoporfin; temsirolimus; teniposide; teroxirone;testolactone; thalidomide; thiamiprine; thioguanine; thiotepa;tiazofurin; tirapazamine; topotecan hydrochloride; toremifene;tositumomab and I 131 Iodine tositumomab; trastuzumab; trestoloneacetate; tretinoin; triciribine phosphate; trimetrexate; trimetrexateglucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;uredepa; valrubicin; vapreotide; verteporfin; vinblastine; vinblastinesulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidinesulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbinetartrate; vinrosidine sulfate; vinzolidine sulfate; vorinostat;vorozole; zeniplatin; zinostatin; zoledronic acid; and zorubicinhydrochloride.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used in combination with anti-emetic agentsto treat nausea or emesis, which result from the use of a compound ofFormula (I), anti-cancer agent(s) and/or radiation therapy.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used in combination with an agent useful inthe treatment of anemia or neutropenia.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered with corticosteroids.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is coadministered with analgesics.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used in combination with radiation therapy(or radiotherapy). Radiation therapy is the treatment of cancer andother diseases with ionizing radiation. Radiation therapy is optionallyused to treat localized solid tumors, such as cancers of the skin,tongue, larynx, brain, breast, prostate, colon, uterus and/or cervix. Itis also optionally used to treat leukemia and lymphoma (cancers of theblood-forming cells and lymphatic system, respectively).

A technique for delivering radiation to cancer cells is to placeradioactive implants directly in a tumor or body cavity. This is calledinternal radiotherapy (brachytherapy, interstitial irradiation, andintracavitary irradiation are types of internal radiotherapy.) Usinginternal radiotherapy, the radiation dose is concentrated in a smallarea, and the patient stays in the hospital for a few days. Internalradiotherapy is frequently used for cancers of the tongue, uterus,prostate, colon, and cervix. The term “radiotherapy” or “ionizingradiation” include all forms of radiation, including but not limited toα, β, and γ radiation and ultraviolet light.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Example 1 Preparation of5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate 1)

A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubberseptum, and a N₂ inlet was charged with 5-bromo-1H-indazole (10 g, 50.7mmol) and anhydrous DCM (101 mL). To this solution, DHP (23 mL, 253.8mmol) was added in one portion at room temperature followed by additionof PPTS (1.28 g, 5 mmol). The resulting mixture was stirred at roomtemperature for 48 h. Upon completion by TLC, the reaction mixture wasquenched with water and extracted with DCM (3×100 mL). The combinedorganic extracts were washed with water (100 mL), washed with brine (50mL), dried over sodium sulfate, filtered, concentrated, and purified bysilica gel chromatography (0-10% ethyl acetate in hexanes) to give thetitle compound (13 g) as a pale yellow oil. ¹H NMR (300 MHz, DMSO-d₆): δ8.10 (s, 1H), 8.02 (d, 1H), 7.73 (d, 1H), 7.53 (dd, 1H), 5.86 (dd, 1H),3.89-3.85 (m, 1H), 3.73-3.69 (m, 1H), 2.43-2.31 (m, 1H), 2.06-1.92 (m,2H), 1.80-1.64 (m, 1H), 1.60-150 (m, 2H).

Example 2 Preparation of5-Ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate 2) Step1: 1-(Tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazole

To a 250-mL pressure tube,5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (11.9 g, 42.3 mmol;Intermediate 1), Pd(Ph₃P)₂Cl₂ (1.48 g, 0.05 mmol), CuI (0.8 g, 4.2 mmol)and THF/triethylamine

(5:1, 85 mL) were added. This mixture was degassed with three vacuum/N₂cycles, and then trimethylsilylacetylene (9 mL, 63.5 mmol) was added.The pressure tube was sealed and heated at 80° C. for 2 days. Uponcompletion by LCMS, the reaction mixture was cooled down to roomtemperature and filtered through Celite with ethyl acetate (200 mL). Thefiltrate was concentrated to give the crude product that was useddirectly in the next step. LCMS: 299 (M+H)⁺.

Note: For this compound and other compounds synthesized using thisreaction, alternate procedures have been employed using an amine, suchas triethylamine or pyrrolidine, as the sole solvent.

Step 2: 5-Ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubberseptum, and a N₂ inlet was charged with a solution of1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazole(12.6 g, 42.2 mmol) in MeOH. To this solution, solid K₂CO₃ (0.58 g, 4.2mmol) was added in one portion. The resulting mixture was stirred atroom temperature for 4 h. Upon completion by TLC, the reaction mixturewas filtered, concentrated, and purified by silica gel chromatography(0-10% ethyl acetate in hexanes) to give the title compound (4.7 g) as apale yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.13 (s, 1H), 7.96 (s,1H), 7.75 (d, 1H), 7.47 (dd, 1H), 5.86 (dd, 1H), 4.10 (s, 1H), 3.90-3.86(m, 1H), 3.78-3.68 (m, 1H), 2.43-2.32 (m, 1H), 2.06-1.93 (m, 2H),1.81-1.66 (m, 1H), 1.60-1.50 (m, 2H).

Example 3 Preparation of5-(But-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate3)

A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubberseptum, and a N₂ inlet was charged with5-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.2 g, 18.6 mmol;Intermediate 2) and anhydrous THF/TMEDA (9:1, 93 mL). This solution wascooled to −78° C. in an IPA/dry ice bath, and n-BuLi (17.4 mL solutionin hexanes, 27.84 mmol) was added dropwise over 15 minutes. Theresulting mixture was stirred for 30 minutes at −78° C., and theniodoethane (2.23 mL, 27.84 mmol) was added dropwise over 5 minutes. Themixture was gradually warmed to room temperature, stirred for 1 h, andthen heated at 40° C. overnight. Upon completion by LCMS, the reactionmixture was cooled to room temperature, quenched with water (100 mL),and extracted with ethyl acetate (2×100 mL). The combined organics werewashed with water (100 mL), washed with brine (50 mL), dried over sodiumsulfate, filtered, concentrated, and purified by silica gelchromatography (0-10% ethyl acetate in hexanes) to give the titlecompound (1.42 g) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ8.08 (s, 1H), 7.82 (s, 1H), 7.69 (d, 1H), 7.39 (d, 1H), 5.84 (dd, 1H),3.89-3.86 (m, 1H), 3.76-3.72 (m, 1H), 2.45-2.36 (m, 3H), 2.04-1.94 (m,2H), 1.74 (m, 1H), 1.57-1.20 (m, 2H), 1.16 (t, 3H); LCMS: 255 (M+H)⁺.

Note: For this compound and other compounds prepared using thisreaction, lithium bis(trimethylsilyl)amide has been employed as the basein THF at 0° C. followed by alkylation with alkyl-halide at reflux.

The Intermediates in Table 2 were prepared from known or commercialstarting materials following the procedures outlined for Intermediates1-3.

TABLE 2 Inter- mediate 4 1-(Tetrahydro- 2H-pyran-2- yl)-5-(4,4,4-trideuterobut- 1-yn-1-yl)- 1H-indazole

Inter- mediate 5 5-(But-1-yn-1- yl)-7-chloro-1- (tetrahydro-2H-pyran-2-yl)- 1H-indazole

Inter- mediate 6 5-(But-1-yn- 1-yl)-7-methyl- 1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole

Inter- mediate 7 5-(But-1-yn-1- yl)-3-methyl- 1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole

Inter- mediate 8 5-(But-1-yn-1- yl)-3-chloro-1- (tetrahydro-2H-pyran-2-yl)- 1H-indazole

Inter- mediate 9 5-(Prop-1-yn- 1-yl)-1- (tetrahydro- 2H-pyran-2-yl)-1H-indazole

Inter- mediate 10 5-(Pent-1- yn-1-yl)-1- (tetrahydro- 2H-pyran-2-yl)-1H- indazole

Inter- mediate 11 5-(Perdeuterobut- 1-yn-1-yl)-1- (tetrahydro-2H-pyran-2-yl)- 1H-indazole

Example 4 Preparation of5-(But-1-yn-1-yl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 12) Step 1:4-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazole

A mixture of 5-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(915 mg, 3.10 mmol; prepared from 5-bromo-4-methyl-1H-indazole followingthe procedure outlined for Intermediate 1), copper iodide (72 mg, 0.38mmol), sodium tetrachloropalladate (55 mg, 0.19 mmol),2-(di-tert-butylphosphino)-1-phenyl-1H-indole (128 mg, 0.379 mmol), andTMEDA:H₂O (9:1, 10 mL) was degassed with three vacuum/nitrogen cycles.Ethynyltrimethylsilane was added to the reaction, and the mixture washeated at 80° C. for 90 min and then cooled to room temperature. Thereaction mixture was filtered through Celite and the Celite was washedwith ethyl acetate (100 mL). The filtrate was washed (2×50 mL sat'dNaHCO₃), dried (Na₂SO₄), and concentrated under reduced pressure. Thecrude material was purified on a silica gel column to yield the desiredcompound. ¹H NMR (300 MHz, DMSO-d₆): δ 8.24 (s, 1H), 7.54 (d, 1H), 7.39(d, 1H), 5.82 (dd, 1H), 3.88 (m, 1H), 3.71 (m, 1H), 2.63 (s, 3H), 2.39(m, 1H), 2.00 (m, 2H), 1.72 (m, 1H), 1.58 (m, 2H), 0.24 (s, 9H); LCMS:313 (M+H)⁺

Step 2:5-(But-1-yn-1-yl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

The title compound was prepared from4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazolefollowing the procedures outlined for Intermediate 2 (step 2) andIntermediate 3. ¹H NMR (300 MHz, DMSO-d₆): δ 7.97 (s, 1H), 7.27 (d, 1H),7.11 (d, 1H), 5.59 (dd, 1H), 3.58 (m, 1H), 3.50 (m, 1H), 2.38 (s, 3H),2.17 (q, 2H), 2.13 (m, 1H), 1.77 (m, 2H), 1.50 (m, 1H), 1.36 (m, 2H),0.98 (t, 3H).

The Intermediate in Table 3 was prepared from5-bromo-6-methyl-1H-indazole following the procedures outlined forIntermediate 12.

TABLE 3 Inter- mediate 13 5-(But-1-yn- 1-yl)-6-methyl- 1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole

Example 5 Preparation of5-(Cyclopropylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 14)

A 1 L three-necked round bottom flask was charged with5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (31.2 g, 111 mmol;Intermediate 1) and triethylamine (500 mL). The flask was degassed withthree vacuum/N₂ cycles, followed by the addition of Pd(PPh₃)₂Cl₂ (7.7 g,11 mmol) and CuI (2.1 g, 11 mmol) under N₂ atmosphere. The flask wasagain degassed with three vacuum/N₂ cycles. Ethynylcyclopropane (70% intoluene, 20.9 g, 222 mmol) was then added via syringe and the reactionmixture was stirred at 80° C. for 16 hours. Upon completion, the solventwas evaporated. The residue was diluted with dichloromethane (600 mL),washed with water (2×200 mL) and brine (200 mL), dried over anhydroussodium sulfate, and concentrated in vacuo. The residue was furtherpurified on silica gel column (1:100-1:20 EtOAc/petroleum ether)affording the title compound (27.0 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.09(s, 1H), 7.82 (s, 1H), 7.70 (d, 1H), 7.39 (m, 1H), 5.84 (dd, 1H),3.91-3.87 (m, 1H), 3.78-3.73 (m, 1H), 2.52-2.37 (m, 1H), 2.05-1.94 (m,2H), 1.76-1.72 (m, 1H), 1.60-1.52 (m, 3H), 0.92-0.87 (m, 2H), 0.78-0.73(m, 2H); LCMS: 267 (M+H)⁺.

Example 6 Preparation of5-(4-Methylpent-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 15)

To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.0 g,10.7 mmol; Intermediate 1), Pd(PPh₃)₂Cl₂ (1.03 g, 1.07 mmol) and CuI(203 mg, 1.07 mmol) in triethylamine (30 mL), was added4-methylpent-1-yne (2.23 g, 27.8 mmol) under N₂ atmosphere. Theresulting mixture was stirred at 80° C. for 16 hours under N₂atmosphere. Upon completion, the reaction mixture was diluted with EtOAcand filtered. The filtrate was washed with water (3×10 mL), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (0˜10% EtOAc in petroleum ether) affordingthe title compound (2.2 g) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H),3.90-3.86 (m, 1H), 3.77-3.73 (m, 1H), 2.42-2.32 (m, 1H), 2.33 (d, 2H),2.05-1.94 (m, 2H), 1.86 (m, 1H), 1.76-1.71 (m, 1H), 1.60-1.54 (m, 2H),1.02 (d, 6H); LCMS: 283 (M+H)⁺.

Example 7 Preparation of3-(1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-ol(Intermediate 16)

A 500 mL three-necked round bottom flask was charged with5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (14.0 g, 50 mmol;Intermediate 1) and triethylamine (300 mL). The flask was degassed with3 cycles of vacuum/N₂, followed by the addition of Pd(PPh₃)₂Cl₂ (3.5 g,5 mmol) and CuI (0.95 g, 5 mmol) under N₂ atmosphere. The flask wasagain degassed with 3 cycles of vacuum/N₂. Prop-2-yn-1-ol (8.4 g, 150mmol) was added via syringe and the reaction mixture was stirred at 80°C. for 16 hours. Upon completion, the solvent was evaporated. Theresidue was diluted with dichloromethane (400 mL), washed with water(3×200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was further purified on silica gelcolumn (1:100-1:20 EtOAc/petroleum ether) affording the title compound(11.1 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.13 (s, 1H), 7.90 (s, 1H), 7.75(d, 1H), 7.44 (d, 1H), 5.86 (dd, 1H), 5.33 (t, 1H), 4.33 (d, 2H),3.89-3.86 (m, 1H), 3.79-3.73 (m, 1H), 2.45-2.35 (m, 1H), 2.05-1.95 (m,2H), 1.80-1.70 (m, 1H), 1.60-1.56 (m, 2H); LCMS: 257 (M+H)⁺.

Example 8 Preparation of:4-(1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol(Intermediate 17)

To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (17.0g, 60.7 mmol; Intermediate 1), Pd(PPh₃)₂Cl₂ (5.80 g, 6.07 mmol), CuI(1.20 g, 6.07 mmol), and triethylamine (170 mL) was added but-3-yn-1-ol(6.80 g, 97.2 mmol) under N₂ atmosphere. The resulting mixture wasstirred at 80° C. for 16 hours under N₂ atmosphere. Upon completion, thereaction mixture was diluted with EtOAc and washed with water (3×50 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (30˜50%EtOAc in petroleum ether) affording the title compound (8.0 g). ¹H NMR(400 MHz, DMSO-d₆): δ 8.09 (s, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.40 (d,1H), 5.84 (dd, 1H), 4.90 (br, 1H), 3.91-3.87 (m, 1H), 3.77-3.70 (m, 1H),3.60 (t, 2H), 2.56 (t, 2H), 2.48-2.33 (m, 1H), 2.04-1.94 (m, 2H),1.76-1.69 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 271 (M+H)⁺.

Example 9 Preparation of5-Bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate18) Step 1: 4-Bromo-3-fluoro-2-methylaniline

To a solution of 3-fluoro-2-methylaniline (20 g, 0.16 mol) in CH₃CN (500mL) was added NBS (31.3 g, 0.176 mol) in portions at 10° C. Theresulting mixture was stirred at room temperature for 30 minutes. Uponcompletion, saturated Na₂S₂O₃ (500 mL) was added slowly into thereaction mixture at 10° C. The organic layer was separated, and theaqueous layer was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo. The residue was washed withpetroleum ether affording the title compound (20 g), which was used inthe next step without further purification. ¹H NMR (300 MHz, DMSO-d₆): δ7.08 (t, 1H), 6.40 (dd, 1H), 5.35 (br, 2H), 1.98 (d, 3H).

Step 2: 5-Bromo-4-fluoro-1H-indazole

To a solution of 4-bromo-3-fluoro-2-methylaniline (20 g, 98.0 mmol) inCH₃CO₂H (600 mL) was added NaNO₂ (8.1 g, 118 mmol) at 10° C. Theresulting mixture was stirred at room temperature for 4 hours. Uponcompletion, aqueous NaOH (50%) was added to the reaction mixture untilpH was ˜7-8. The mixture was extracted with EtOAc. The organic layer wasdried over Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (0˜40% EtOAc in petroleum ether)affording the title compound (16 g). ¹H NMR (300 MHz, DMSO-d₆): δ 13.58(br, 1H), 8.22 (s, 1H), 7.53 (t, 1H), 7.38 (d, 1H).

Step 3: 5-Bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of 5-bromo-4-fluoro-1H-indazole (50 g, 0.23 mol) and DHP(23 g, 0.28 mol) in dry dichloromethane (1000 mL) was added PTSA (2.2 g,11.5 mmol) at room temperature. The resulting mixture was stirredovernight at that temperature. Upon completion, saturated aqueous NaHCO₃(100 mL) was added slowly into the reaction mixture. The organic layerwas separated, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (0˜2% EtOAc inpetroleum ether) and then re-crystallized from petroleum ether to affordthe title compound (55 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.28 (s, 1H),7.58-7.66 (m, 2H), 5.89 (dd, 1H), 3.90-3.85 (m, 1H), 3.79-3.70 (m, 1H),2.42-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.77-1.68 (m, 1H), 1.60-1.53 (m,2H); LCMS: 299 (M+H)⁺.

Example 10 Preparation of5-(Cyclopropylethynyl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 19)

In a high pressure tube, a mixture of5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.0 g, 26.8mmol; Intermediate 18), PdCl₂(PPh₃)₂ (3.7 g, 5.35 mmol), CuI (1.0 g,5.35 mmol), and triethylamine (30 mL) was deoxygenated with three cyclesof vacuum/nitrogen. Ethynylcyclopropane (8.9 g, 134 mmol) was addedunder N₂ atmosphere. The tube was sealed and the reaction mixture washeated at 120° C. for 63 hours. Upon completion, the reaction mixturewas diluted with ethyl acetate and filtered through Celite. The filtratewas concentrated in vacuo and the residue was purified by columnchromatography on silica gel (0˜10% ethyl acetate in petroleum ether)affording the title compound (4.3 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.25(s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 5.88 (dd, 1H), 3.88-3.85 (m, 1H),3.76-3.73 (m, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.76-1.72 (m,1H), 1.62-1.56 (m, 3H), 0.93-0.89 (m, 2H), 0.79-0.74 (m, 2H); LCMS: 285(M+H)⁺.

The Intermediates in Table 4 were prepared from Intermediate 1 followingthe procedures outlined for Intermediates 14-17, and 19.

TABLE 4 Inter- mediate 20 5-(Cyclo- pentyl- ethynyl)-1- (tetrahydro-2H-pyran- 2-yl)-1H- indazole

Inter- mediate 21 5-(Cyclo- hexyl- ethynyl)-1- (tetrahydro- 2H-pyran-2-yl)-1H- indazole

Inter- mediate 22 5-(3- Methylbut- 1-yn-1-yl)- 1-(tetra- hydro-2H-pyran-2- yl)-1H- indazole

Inter- mediate 23 5-(Hex-1- yn-1-yl)-1- (tetra- hydro-2H- pyran-2-yl)-1H- indazole

Inter- mediate 24 5-(3-Cyclo- pentylprop- 1-yn-1-yl)- 1-(tetra-hydro-2H- pyran-2- yl)-1H- indazole

Example 11 Preparation of5-(4-Chlorobut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 25)

To a solution of4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g,3.7 mmol; Intermediate 17) in dry pyridine (10 mL) was added dropwisePOCl₃ (2.4 g, 14.7 mmol) under N₂ atmosphere. The resulting solution wasstirred at room temperature for 16 hours. Upon completion, the reactionmixture was concentrated in vacuo. The residue was poured into ice-waterand extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was further purified on silica gel column (0˜20% EtOAc inpetroleum ether) affording the title compound (400 mg). ¹H NMR (400 MHz,DMSO-d₆): δ 8.11 (s, 1H), 7.86 (s, 1H), 7.72 (d, 1H), 7.42 (dd, 1H),5.86 (dd, 1H), 3.90-3.86 (m, 1H), 3.81 (t, 2H), 3.77-3.70 (m, 1H), 2.93(t, 2H), 2.41-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.75-1.71 (m, 1H),1.60-1.55 (m, 2H); LCMS: 289 (M+H)⁺.

Example 12 Preparation of5-(3,3-Difluoroprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 26) Step 1:3-(1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propiolaldehyde

A 500 mL three-necked round bottom flask was charged with3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-ol (11.4 g,44.2 mmol; Intermediate 16), dichloromethane (300 mL) and MnO₂ (38.4 g,44.2 mmol). The resulting mixture was stirred at room temperature for 16hours. Upon completion, the reaction mixture was filtered. The filtratewas dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (1:100-1:20EtOAc/petroleum ether) affording the title compound (6.4 g). ¹H NMR (400MHz, DMSO-d₆): δ 9.45 (s, 1H), 8.27-8.25 (m, 2H), 7.87 (d, 1H), 7.66(dd, 1H), 5.86 (dd, 1H), 3.91-3.87 (m, 1H), 3.79-3.72 (m, 1H), 2.40-2.36(m, 1H), 2.05-1.96 (m, 2H), 1.78-1.72 (m, 1H), 1.61-1.56 (m, 2H); LCMS:255 (M+H)⁺.

Step 2:5-(3,3-Difluoroprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

A 500 mL round bottom flask was charged with dry dichloromethane (200mL), triethylamine-3HF (8.06 g, 50.1 mmol) and XtalFluor-E (8.61 g, 37.6mmol) under N₂ atmosphere. The resulting solution was stirred at roomtemperature for 10 minutes.3-(1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propiolaldehyde (3.21 g,12.5 mmol) was added, and the mixture was stirred at room temperaturefor 1 hour. Upon completion, saturated NaHCO₃ (100 mL) was added intothe mixture. The organic layer was separated, and the aqueous layer wasextracted with dichloromethane (2×100 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (1:100-1:20EtOAc/petroleum ether) affording the title compound (1.71 g). ¹H NMR(400 MHz, DMSO-d₆): δ 8.20 (s, 1H), 8.14 (s, 1H), 7.83 (d, 1H), 7.58(dd, 1H), 6.99 (t, 1H), 5.90 (dd, 1H), 3.90-3.87 (m, 1H), 3.79-3.73 (m,1H), 2.45-2.37 (m, 1H), 2.05-1.96 (m, 2H), 1.79-1.65 (m, 1H), 1.60-1.56(m, 2H); LCMS: 277 (M+H)⁺.

Example 13 Preparation of5-(4-Fluorobut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 27)

To a solution of4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g,3.7 mmol; Intermediate 17) in dry dichloromethane (25 mL), was addedtriethylamine-3HF (1.2 g, 7.4 mmol). XtalFluor-E (1.2 g, 5.5 mmol) wasthen added. The resulting solution was stirred at room temperature for30 minutes. Upon completion, the reaction solution was neutralized byslow addition of saturated NaHCO₃ (10 mL). The organic layer was driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (0˜20% EtOAc in petroleum ether)affording the title compound (100 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.12(s, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60(dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m,1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, 1H), 1.58 (m, 2H); LCMS: 273(M+H)⁺.

Example 14 Preparation of1-(Tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)-1H-indazole(Intermediate 28) Step 1: 5-Iodo-1H-indazole

To a solution of 4-iodo-2-methylaniline (1.09 g, 4.68 mmol) in CH₃CO₂H(40 mL), were added NaNO₂ (0.39 g, 5.65 mmol) and water (1 mL) at 10° C.The resulting mixture was stirred at room temperature for 6 hours. Uponcompletion, the reaction mixture was extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (0˜40% EtOAcin petroleum ether) affording the title compound (0.90 g). ¹H NMR(DMSO-d₆, 400 MHz): δ 13.23 (br, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.57(d, 1H), 7.41 (d, 1H).

Step 2: 5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of 5-iodo-1H-indazole (0.90 g, 3.69 mmol) and DHP (1.57 g,18.7 mmol) in dry dichloromethane (20 mL), was added PTSA (0.08 g, 0.41mmol) at room temperature. The resulting mixture was stirred overnight.Upon completion, saturated aqueous NaHCO₃ (30 mL) was added slowly intothe reaction mixture. The organic layer was separated, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (0-5% EtOAc in petroleum ether) affordingthe title compound (1.0 g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (s, 1H),8.08 (s, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 5.85 (dd, 1H), 3.88-3.85 (m,1H), 3.78-3.72 (m, 1H), 2.41-2.29 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.72(m, 1H), 1.61-1.56 (m, 2H).

Step 3:1-(Tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)-1H-indazole

To a solution of LDA (2 M in THF, 3.2 mL, 6.4 mmol) in anhydrous THF (10mL) was added dropwise 2-bromo-3,3,3-trifluoroprop-1-ene (0.55 g, 3.1mmol) at −78° C. The resulting mixture was stirred at that temperaturefor 15 minutes, followed by the addition of ZnCl₂ (1 M in ethyl ether,6.5 mL, 6.5 mmol) and TMEDA (1 mL, 6.5 mmol). The mixture was stirred at−78° C. for further 30 minutes and then 30 minutes at room temperature.5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.99 g, 3.0 mmol) andPd(PPh₃)₄ (0.21 g, 0.18 mmol) were added. The reaction mixture washeated at 80° C. for 6 hours under N₂ atmosphere. Upon completion, thereaction mixture was quenched with water (100 mL) and then diluted withethyl acetate (300 mL). The organic layer was separated, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (0˜20% EtOAc in petroleum ether) affordingthe title compound (299 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 8.28 (s, 1H),8.24 (s, 1H), 7.87 (d, 1H), 7.68 (dd, 1H), 5.91 (dd, 1H), 3.90-3.86 (m,1H), 3.79-3.72 (m, 1H), 2.41-2.36 (m, 1H), 2.05-1.96 (m, 2H), 1.76-1.72(m, 1H), 1.60-1.56 (m, 2H); LCMS: 295 (M+H)⁺.

Example 15 Preparation of5-(4-Chlorobut-1-yn-1-yl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 29) Step 1:4-(4-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol

To a mixture of5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.80 g, 9.36mmol, Intermediate 18), Pd(PPh₃)₂Cl₂ (660 mg, 0.94 mmol), CuI (180 mg,0.94 mmol), and triethylamine (50 mL) was added but-3-yn-1-ol (2.0 g,28.1 mmol) under N₂ atmosphere. The resulting mixture was stirred at 60°C. for 16 hours. Upon completion, the reaction mixture was diluted withEtOAc, and washed with water (3×10 mL). The organic layer was dried overNa₂SO₄ and concentrated in vacuo. The residue was purified on silica gelcolumn (0˜20% EtOAc in petroleum ether) affording the title compound(2.0 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.33 (s, 1H), 7.64 (d, 1H), 7.49(dd, 1H), 5.94 (dd, 1H), 4.99 (t, 1H), 3.98-3.92 (m, 1H), 3.85-3.77 (m,1H), 3.68 (t, 2H), 2.67 (t, 2H), 2.48-2.35 (m, 1H), 2.12-2.02 (m, 2H),1.84-1.78 (m, 1H), 1.68-1.62 (m, 2H).

Step 2:5-(4-Chlorobut-1-yn-1-yl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol(4.6 g, 16.0 mmol) in pyridine (50 mL), was added POCl₃ (10.3 g, 67.3mmol). The resulting solution was stirred at room temperature for 2hours. Upon completion, the reaction solution was poured into water (250mL) and extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated in vacuo. The residue was purified on silica gel column(0˜10% EtOAc in petroleum ether) affording the title compound (2.62 g).¹H NMR (300 MHz, DMSO-d₆): δ 8.13 (s, 1H), 7.58 (d, 1H), 7.43 (dd, 1H),5.87 (dd, 1H), 3.90-3.69 (m, 2H), 3.83 (t, 2H), 2.98 (t, 1H), 2.41-2.29(m, 1H), 2.06-1.94 (m, 2H), 1.78-1.70 (m, 1H), 1.60-1.54 (m, 2H); LCMS:307 (M+H)⁺.

Example 16 Preparation of4-Fluoro-5-(4-fluorobut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 30)

To a solution of4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol(3.4 g, 11.8 mmol; Intermediate 29, Step 1) in dry dichloromethane (100mL), was added triethylamine-3HF (7.6 g, 47.2 mmol). XtalFluor-E (8.0 g,34.9 mmol) was then added. The resulting solution was stirred at roomtemperature for 30 minutes. Upon completion, the reaction solution wasneutralized by slow addition of saturated NaHCO₃ (30 mL). The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (0˜20% EtOAc inpetroleum ether), and then re-crystallized from petroleum ether toafford the title compound (1.3 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.27 (s,1H), 7.58 (d, 1H), 7.44 (dd, 1H), 5.89 (dd, 1H), 4.60 (dt, 2H),3.91-3.85 (m, 1H), 3.80-3.69 (m, 1H), 2.93 (dt, 2H), 2.46-2.28 (m, 1H),2.06-1.95 (m, 2H), 1.78-1.67 (m, 1H), 1.60-1.52 (m, 2H); LCMS: 291(M+H)⁺.

Example 17 Preparation of:5-(3-Methoxyprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 31)

Sodium hydride (60% in mineral oil, 0.42 g, 10.5 mmol) was added to asolution of3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)prop-2-yn-1-ol (1.01 g,3.94 mmol; Intermediate 16) in THF (20 mL) at 0° C. The mixture wasstirred at 0° C. for 30 minutes, and then iodomethane (1.67 g, 11.8mmol) was added. The resulting mixture was stirred at room temperaturefor 16 h. The reaction mixture was poured into ice water (100 mL) andextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine (100 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (EtOAc/petroleum ether=1:30) to afford the title compound(0.714 g, yield 67.3%). ¹H NMR (DMSO-d₆, 300 MHz): δ 8.21 (s, 1H), 7.93(s, 1H), 7.73 (d, 1H), 7.47-7.45 (m, 1H), 5.85-5.83 (m, 1H), 4.38 (s,2H), 3.76-3.71 (m, 2H), 3.35 (s, 3H), 2.40-2.37 (m, 1H), 2.03-1.94 (m,2H), 1.73-1.72 (m, 1H), 1.57-1.55 (m, 2H). LCMS: 271 (M+H)⁺.

The Intermediates in Table 5 were prepared from Intermediate 1 followingthe procedures outlined for Intermediates 16, 17 & 31.

TABLE 5 Inter- mediate 32 5-(4- Methoxy- but-1-yn- 1-yl)-1- (tetrahydro-2H-pyran- 2-yl)-1H- indazole

Inter- mediate 33 5-(5- Methoxy- pent-1-yn- 1-yl)-1- (tetrahydro-2H-pyran- 2-yl)-1H- indazole

Inter- mediate 34 5-(6- Methoxy- hex-1-yn- 1-yl)-1- (tetrahydro-2H-pyran- 2-yl)-1H- indazole

Example 18 Preparation of But-1-yn-1-yltrimethylsilane (Intermediate 35)

A 3 L three-necked round bottom flask was charged with(trimethylsilyl)acetylene (116 g, 1.19 mol) and dry THF (400 mL). Thesolution was cooled to −78° C. To this solution, butyllithium in hexane(2.5 M, 500 mL, 1.25 mol) was added dropwise over 2 hours. The resultingmixture was warmed to 0° C. for 10 minutes and then re-cooled to −78° C.HMPA (234 g, 1.31 mol) was added, and the mixture was stirred at −78° C.for 30 minutes. To this solution, iodoethane (200 g, 1.28 mol) wasadded. The reaction mixture was allowed to warm to room temperature andstirred overnight. Upon completion, the reaction mixture was washed withwater (4×600 mL) and then brine (2×500 mL). The organic layer was driedover anhydrous sodium sulfate and filtered. Hexane and THF weredistilled off at 75˜110° C. But-1-yn-1-yltrimethylsilane was distilledbetween 125 to 135° C. affording 91 g of a colorless liquid (61%). ¹HNMR (400 MHz, DMSO-d₆) δ 2.20 (q, 2H), 1.05 (t, 3H), 0.11 (s, 9H); ¹³CNMR (100 MHz, CDCl₃): δ 108.8, 83.3, 13.7, 13.4, 0.0.

Example 19 Alternate Preparation of Intermediate 3

A mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (39.6 g,0.142 mol; Intermediate 1), Cs₂CO₃ (60.0 g, 184 mmol), CuI (1.35 g, 7.08mmol), Pd(OAc)₂ (1.59 g, 7.08 mmol), dppf (3.93 g, 7.08 mmol), and DMA(160 mL) was degassed with three vacuum/nitrogen cycles.But-1-yn-1-yltrimethylsilane (23.2 g, 184 mmol; Intermediate 35) wasadded, and the resulting mixture was heated at 80° C. for 5 h under N₂.Upon completion by LCMS, the reaction mixture was diluted with EtOAc(300 mL) and H₂O (300 mL) and then filtered. The organic layer of thefiltrate was separated, and the aqueous layer was extracted with EtOAc(3×150 mL). The combined organic layers were washed with brine (2×100mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified on silica gel column (300-400 mesh, 20 cm in diameter and15 cm in height) using EtOAc/petroleum ether (1 L of petroleum ether;then 1 L of EtOAc/petroleum ether=1/50; and then EtOAc/Petroleumether=1/30 until the by-product was washed out; then EtOAc/petroleumether=1/10 to collect the product) affording a yellow oil (33 g) whichsolidified over time in the 4° C. refrigerator. The resulting solid wasfurther washed with petroleum ether (200 mL, then 3×50 mL) affording thetitle compound as an off-white solid (26 g, 73%).

Example 20 Preparation of5-(But-1-yn-1-yl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 36)

Nitrogen was bubbled into a solution of5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (19.7 g, 65.9mmol; Intermediate 18) and DMA (60 mL). After 5 min, CuI (1.25 g, 6.6mmol), Pd(OAc)₂ (1.48 g, 6.6 mmol), dppf (3.66 g, 6.6 mmol), Cs₂CO₃(34.3 g, 105.4 mmol), and but-1-yn-1-yltrimethylsilane (11.6 g, 92.3mmol; Intermediate 35) were added sequentially with continued N₂bubbling. The resulting mixture was heated at 80° C. for 18 h under N₂.The reaction mixture was diluted with EtOAc (900 mL) and H₂O (500 mL)and then filtered. The organic layer of the filtrate was separated, andthe aqueous layer was extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with brine (3×100 mL), dried over anhydrousNa₂SO₄, concentrated, and purified by silica gel chromatography (1:30EtOAc/petroleum ether) to give the title compound (15.2 g) as a whitesolid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.26 (s, 1H), 7.57 (d, 1H), 7.42(dd, 1H), 5.87 (dd, 1H), 3.90-3.86 (m, 1H), 3.78-3.71 (m, 1H), 2.48 (q,2H), 2.40-2.30 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.71 (m, 1H), 1.59-1.57(m, 2H), 1.19 (t, 3H); LCMS: 273 (M+H)⁺.

Example 21 Preparation of5-(But-1-yn-1-yl)-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 37) Step 1: 4-Bromo-3-chloro-2-methylaniline

To a solution of 3-chloro-2-methylaniline (30 g, 0.212 mol) in CH₃CN(300 mL) was added NBS (45.2 g, 0.254 mol) in portions at 10° C. Theresulting mixture was stirred at room temperature for 30 minutes. Uponcompletion, saturated Na₂S₂O₃ (500 mL) was added slowly into thereaction mixture at 10° C. The organic layer was separated, and theaqueous layer was extracted with EtOAc. The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo. The residue was washed withpetroleum ether to afford the title compound (30 g), which was used inthe next step without further purification. ¹H NMR (300 MHz, CDCl₃): δ7.24 (d, 1H), 6.48 (d, 1H), 3.70 (br, 2H), 2.28 (s, 3H).

Step 2: 5-Bromo-4-chloro-1H-indazole

To a solution of 4-bromo-3-chloro-2-methylaniline (11 g, 49.9 mmol) inCH₃CO₂H (450 mL) was added NaNO₂ (5.4 g, 78.3 mmol) in H₂O (15 mL) at10° C. The resulting mixture was stirred at room temperature for 30minutes. Upon completion, the reaction mixture was diluted with H₂O (500mL) and extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated in vacuo. The residue was triturated with petroleumether affording the title compound (4.5 g) as yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d,1H).

Step 3: 5-Bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of 5-bromo-4-chloro-1H-indazole (8.0 g, 34.6 mmol) and DHP(8.72 g, 0.104 mol) in dry dichloromethane (200 mL) was added PTSA(0.657 g, 3.46 mmol) at room temperature. The resulting mixture wasstirred at room temperature overnight. Upon completion, saturatedaqueous NaHCO₃ (100 mL) was added slowly to the reaction mixture. Theorganic layer was separated, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by column chromatography on silica gel(0-3% EtOAc in petroleum ether) affording the title compound (8.9 g). ¹HNMR (300 MHz, DMSO-d₆): δ 8.19 (s, 1H), 7.71 (m, 2H), 5.88 (dd, 1H),3.89-3.84 (m, 1H), 3.79-3.73 (m, 1H), 2.42-2.32 (m, 1H), 2.05-1.95 (m,2H), 1.75-1.70 (m, 1H), 1.60-1.54 (m, 2H).

Step 4:5-(But-1-yn-1-yl)-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

In a 20 mL microwave tube, nitrogen was bubbled through triethylamine (6mL) for 10 minutes.

5-bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.00 g, 6.34mmol), tetrabutylammonium fluoride (3.70 g, 14.3 mmol), CuI (0.24 g, 1.3mmol) and Pd(PPh₃)₄ (1.46 g, 1.26 mmol) were added under nitrogenatmosphere, and bubbling of nitrogen was continued for another 5minutes. But-1-yn-1-yltrimethylsilane (1.80 g, 14.3 mmol; Intermediate35) was then added and the tube was sealed immediately. The reactionmixture was heated in a microwave reactor at 120° C. for 3 hours. Fourof these reactions (4×2 g scale per run) were combined, mixed with water(100 mL), and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (0-3% ethylacetate in petroleum ether) affording the title compound (4.5 g, 90%),which was then triturated with petroleum ether (8 mL). The solid wascollected and dried to afford a pale yellow powder (3.5 g). This powderwas re-crystallized from ethyl acetate (2 mL) to afford the pure titlecompound as pale yellow crystals (3.0 g). ¹H NMR (400 MHz, DMSO-d₆): δ8.19 (s, 1H), 7.72 (d, 1H), 7.49 (d, 1H), 5.88 (dd, 1H), 3.89-3.85 (m,1H), 3.79-3.73 (m, 1H), 2.50 (q, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m,2H), 1.75-1.70 (m, 1H), 1.60-1.55 (m, 2H), 1.21 (t, 3H); LCMS: 289(M+H)⁺.

Example 22 Preparation of5-(But-1-yn-1-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 38) Step 1: 5-Bromo-2,3-difluorobenzaldehyde

To a solution of 2,3-difluorobenzaldehyde (42 g, 0.296 mol) in H₂SO₄(150 mL), was added NBS (63 g, 0.354 mol) in three portions over aperiod of 30 minutes at 60° C. The resulting mixture was heated for 6hours at this temperature under N₂. Work-up: the reaction mixture waspoured into ice water. Petroleum ether (300 mL) was added, and themixture was stirred for 10 minutes. The organic layer was separated, andthe aqueous layer was extracted with more petroleum ether (300 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography on silica gel(0-0.5% EtOAc in petroleum ether) to give5-bromo-2,3-difluorobenzaldehyde (17.4 g). ¹H NMR (300 MHz, CDCl₃): δ10.32 (s, 1H), 7.81-7.79 (m, 1H), 7.65-7.60 (m, 1H).

Step 2: (E)-5-Bromo-2,3-difluorobenzaldehyde O-methyl oxime

A mixture of 5-bromo-2,3-difluorobenzaldehyde (17.38 g, 78.6 mmol),O-methylhydroxylamine hydrochloride (7.23 g, 86.46 mmol), and K₂CO₃ (13g, 94.32 mmol) in DME (80 mL) was heated at 40° C. for 14 h. Work-up:the reaction mixture was filtered. The filtrate was concentrated invacuo, and the residue was purified by column chromatography on silicagel (0-2% EtOAc in petroleum ether), to give(E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65 g). ¹H NMR(CDCl₃, 300 MHz): δ 8.20 (s, 1H), 7.76-7.73 (m, 1H), 7.35-7.29 (m, 1H),4.01 (s, 3H).

Step 3: 5-Bromo-7-fluoro-1H-indazole

A mixture of (E)-5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (19.65g, 78.6 mmol), hydrazine hydrate (80 mL), and dry THF (80 mL), washeated at 90° C. for 84 h. Work-up: the organic solvent was evaporated.The resulting mixture was diluted with EtOAc (400 mL), washed with water(150 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (0˜20% EtOAc inpetroleum ether) to give 5-bromo-7-fluoro-1H-indazole as a white solid(9.3 g). ¹H NMR (300 MHz, CDCl₃): δ 13.83 (br, 1H), 8.16 (s, 1H), 7.87(s, 1H), 7.45 (d, 1H).

Step 4: 5-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of 5-bromo-7-fluoro-1H-indazole (9.3 g, 43.26 mmol) and DHP(4.36 g, 51.9 mmol) in dry dichloromethane (100 mL), was added PTSA (424mg, 2.16 mmol) at room temperature. The resulting mixture was stirredovernight. Work-up: saturated aqueous NaHCO₃ (30 mL) was slowly added tothe reaction mixture. The organic layer was separated, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (0˜10% EtOAc in petroleum ether) to give5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as a lightyellow solid. (7.8 g). ¹H NMR (300 MHz, CDCl₃): δ 7.98 (s, 1H), 7.64 (s,1H), 7.22 (dd, 1H), 5.84 (dd, 1H), 4.07-4.02 (m, 1H), 3.78-3.71 (m, 1H),2.62-2.53 (m, 1H), 2.16-2.07 (m, 2H), 1.79-1.71 (m, 2H), 1.63-1.33 (m,1H).

Step 5:5-(But-1-yn-1-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Nitrogen was bubbled into a solution of5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7.5 g, 25.33mmol) and DMA (100 mL). After 5 min, CuI (241 mg, 1.27 mmol), Pd(OAc)₂(284 mg, 1.27 mmol), dppf (704 mg, 1.27 mmol), K₂CO₃ (4.89 g, 35.46mmol), and but-1-yn-1-yltrimethylsilane (4.46 g, 35.46 mmol) were addedsequentially with continued N₂ bubbling. The resulting mixture washeated at 80° C. for 10 h under N₂. The reaction mixture was dilutedwith EtOAc (250 mL) and H₂O (200 mL) and filtered. The organic layer ofthe filtrate was separated, and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organic layers were washed with brine(3×50 mL), dried over anhydrous Na₂SO₄, concentrated, and purified bysilica gel chromatography (1:30 EtOAc/petroleum ether) to give the pureproduct as a yellow solid (3.6 g) and an impure product (2 g; furtherpurified to give additional 1.47 g). ¹H NMR (300 MHz, DMSO-d₆): δ 8.19(d, 1H), 7.68 (d, 1H), 7.26 (dd, 1H), 5.79 (dd, 1H), 3.92-3.87 (m, 1H),3.69-3.60 (m, 1H), 2.47-2.34 (m, 1H), 2.43 (q, 2H), 2.07-2.02 (m, 2H),1.76-1.69 (m, 1H), 1.57-1.50 (m, 2H), 1.17 (t, 3H); LCMS: 273 (M+H)⁺.

Example 23 Preparation of5-Bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Intermediate39) Step 1: 5-Bromo-3-fluoro-1H-indazole

A mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g,35.7 mmol; Intermediate 1), acetic acid (4 mL), Selectfluor (25.3 g,71.4 mmol), and acetonitrile (100 mL) was refluxed under N₂ for 2 h. Thereaction was allowed to cool to rt, diluted with ethyl acetate (420 mL),and then washed with water (270 mL). The organic layer was dried overNa₂SO₄ and concentrated in vacuo. The residue was purified on a silicagel column using EtOAc in petroleum ether (1:20) to afford the titlecompound as yellow solids (6.0 g, yield 78.1%). ¹H NMR (DMSO-d₆, 400MHz): δ 12.77 (s, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.48 (d, 1H).

Step 2: 5-Bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

A mixture of 5-bromo-3-fluoro-1H-indazole (6.0 g, 27.9 mmol), PTSA(530.7 mg, 2.79 mmol) and DHP (3.05 g, 36.3 mmol) in dichloromethane (80mL) was stirred at room temperature for 18 h. The reaction mixture wasdiluted with dichloromethane (370 mL) and washed with water (230 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified on a silica gel column using EtOAc in petroleumether (1:100 to 1:15) to afford the title compound as a yellow solid(6.2 g, yield 74.3%). ¹H NMR (DMSO-d₆, 400 MHz): δ 7.96 (s, 1H), 7.70(d, 1H), 7.60 (d, 1H), 5.76 (dd, 1H), 3.84-3.80 (m, 1H), 3.71-3.64 (m,1H), 2.20-2.15 (m, 1H), 1.97-1.87 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.47(m, 2H).

Example 24 Preparation of5-(But-1-yn-1-yl)-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 40)

A 100 mL round bottom flask was charged with5-bromo-3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.2 g, 20.7mmol; Intermediate 39), DMA (20 mL), CuI (393.3 mg, 2.07 mmol), Pd(OAc)₂(465.0 mg, 2.07 mmol), dppf (1.1 g, 2.07 mmol), Cs₂CO₃ (10.8 g, 33.1mmol), and but-1-yn-1-yltrimethylsilane (3.4 g, 26.9 mmol; Intermediate35) sequentially while N₂ was bubbled through the solution. Theresulting mixture was heated at 80° C. for 10 h under N₂. The reactionmixture was diluted with EtOAc (350 mL) and H₂O (300 mL) and filtered.The organic layer of the filtrate was separated, and the aqueous layerwas extracted with EtOAc (2×50 mL). The combined organic layers werewashed with brine (3×100 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was purified on a silica gel columnusing EtOAc in petroleum ether (1:30) to afford the title compound as ayellow solid (3.9 g, yield 69.1%). ¹H NMR (DMSO-d₆, 400 MHz): δ7.76-7.71 (m, 2H), 7.49 (d, 1H), 5.79 (dd, 1H), 3.88-3.85 (m, 1H),3.74-3.71 (m, 1H), 2.44 (q, 2H), 2.24-2.21 (m, 1H), 2.01-1.91 (m, 2H),1.70-1.65 (m, 1H), 1.57-1.54 (m, 2H), 1.18 (t, 3H); LCMS: 273 (M+H)⁺.

Example 25 Preparation of5-(3-Cyclopropylprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 41) Step 1: (3-Cyclopropylprop-1-yn-1-yl)trimethylsilane

A 500 mL three-necked round bottom flask was charged with(trimethylsilyl)acetylene (15 g, 153 mmol) and dry THF (75 mL). Thesolution was cooled to −78° C., and a solution of n-butyllithium inhexane (2.5 M, 75 mL, 188 mmol) was added dropwise over 30 minutes. Theresulting mixture was stirred at 0° C. for 10 minutes and then re-cooledto −78° C. HMPA (40 g, 223 mmol) was added, and the mixture was stirredat −78° C. for 30 minutes. (Bromomethyl)cyclopropane (20.6 g, 153 mmol)was then added. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. Upon completion, the reaction mixturewas washed with water (4×100 mL) and brine (2×100 mL) sequentially. Theorganic layer was dried over anhydrous sodium sulfate. Hexane and THFwas distilled off at 75110° C. then distillation at 138142° C. affordedthe title compound (12 g). ¹H NMR (400 MHz, DMSO-d₆): δ 2.27 (d, 2H),0.91-0.84 (m, 1H), 0.43-0.34 (m, 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H).

Step 2:5-(3-Cyclopropylprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.0 g,14.3 mmol; Intermediate 1), Pd(PPh₃)₂Cl₂ (1.0 g, 1.43 mmol), CuI (271mg, 1.43 mmol), TBAF (11.2 g, 42.8 mmol), triethylamine (20 mL), and THF(20 mL), was added (3-cyclopropylprop-1-yn-1-yl)trimethylsilane (7.9 g,42.8 mmol) under N₂ atmosphere. The resulting mixture was stirred at 80°C. for 16 hours under N₂ atmosphere. Upon completion, the reactionmixture was diluted with EtOAc and filtered. The filtrate was washedwith water (3×10 mL), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (0˜10% EtOAcin petroleum ether) affording the title compound as yellow solid (3.4g). ¹H NMR (400 MHz, DMSO-d₆): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d,1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.89-3.86 (m, 1H), 3.77-3.70 (m, 1H),2.49 (d, 2H), 2.43-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.79-1.71 (m, 1H),1.60-1.55 (m, 2H), 1.06-0.96 (m, 1H), 0.52-0.46 (m, 2H), 0.30-0.25 (m,2H); LCMS: 281 (M+H)⁺.

Example 26 Preparation of (Cyclobutylethynyl)trimethylsilane(Intermediate 42) Step 1: (6-Chlorohex-1-yn-1-yl)trimethylsilane

To a solution of 6-chlorohex-1-yne (100 mL, 94.6 g, 0.82 mol) inanhydrous Et₂O (500 mL) at −78° C., n-butyllithium (2.5 M in hexane, 360mL, 0.90 mol) was added over 40 minutes. The resulting mixture wasstirred for 30 minutes at −78° C. Chlorotrimethylsilane (125 mL, 1.0mol) was then added. The mixture was allowed to warm to room temperatureand stirred for 16 h. The reaction mixture was carefully quenched withsaturated aqueous NH₄Cl (300 mL) at room temperature and extracted withEt₂O (2×200 mL). The combined organic layers were washed with brine (200mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo to affordthe title compound (144 g, yield 93%). ¹H NMR (DMSO-d₆, 400 MHz): δ 3.65(t, 2H), 2.25 (t, 2H), 1.82-1.75 (m, 2H), 1.58-1.51 (m, 2H), 0.12 (s,9H).

Step 2: (Cyclobutylethynyl)trimethylsilane

To a solution of diisopropylamine (153 g, 1.52 mol) in anhydrous THF(1.0 L) at 0° C., n-butyllithium (2.5 M in hexane, 608 mL, 1.52 mol) wasadded dropwise. The mixture was stirred for 20 minutes at 0° C. and thencooled to −78° C. To this mixture, a solution of(6-chlorohex-1-yn-1-yl)trimethylsilane (144 g, 0.76 mol) in anhydrousTHF (200 mL) was added dropwise. The resulting mixture was allowed towarm to room temperature and stirred for 16 h. The reaction mixture wascarefully quenched at room temperature with saturated aqueous NH₄Cl (500mL), and then extracted with pentane (2×200 mL). The combined organiclayers were washed with brine (500 mL) and dried over anhydrous Na₂SO₄.The solvent was evaporated on a rotary evaporator. The residue wasdistilled at 160-162° C./760 Torr to afford the title compound as acolorless liquid (81 g, yield 70%). ¹H NMR (CDCl₃, 400 MHz): δ 3.05-3.01(m, 1H), 2.26-2.20 (m, 2H), 2.17-2.10 (m, 2H), 1.93-1.84 (m, 2H), 0.11(s, 9H).

Example 27 Preparation of5-(Cyclobutylethynyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(Intermediate 43)

A 100 mL round bottom flask was charged with5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol;Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)₂ (0.55 g,2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs₂CO₃ (11.2 g, 34.4 mmol), and(cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 42)sequentially while N₂ was bubbled through the mixture. The resultingmixture was heated at 80° C. under N₂ atmosphere for 2 hours. Thereaction mixture was cooled to room temperature, diluted with EtOAc (100mL) and H₂O (100 mL) and filtered. The organic layer of the filtrate wasseparated, and the aqueous layer was extracted with additional EtOAc(2×50 mL). The combined organic layers were washed with brine (3×100mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residuewas purified on a silica gel column using 0˜10% EtOAc in petroleum etherto afford the title compound as yellow oil (4.8 g, 71%). ¹H NMR(DMSO-d₆): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H),5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H),2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m,1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)⁺.

The Intermediate in Table 6 was prepared from Intermediate 39 & 42following the procedure outlined for Intermediate 43.

TABLE 6 Inter- mediate 44 5-(Cyclo- butylethynyl)-3- fluoro-1-(tetrahydro- 2H-pyran-2- yl)-1H-indazole

General Procedure A: Installation of the Tetrahydropyran (THP)Protecting Group for the Indazole NH.

3,4-Dihydro-2H-pyran (1.1-10 equiv) was added to a solution of theappropriate halo-indazole (1.0 equiv), PPTS (or pTsOH, 0.05-0.3 equiv),and dichloromethane (−2 mL/mmol) at room temperature. The reaction wasstirred under N₂ for 6-48 h (until complete by TLC or LCMS), quenchedwith water, and then extracted with dichloromethane. The extracts weredried, filtered, concentrated, and purified by silica gel chromatographyto give the protected halo-indazole.

General Procedure B: Coupling of the Protected Halo-Indazoles withAlkynyl-Trimethylsilanes

A mixture of the appropriate protected halo-indazole (1.0 equiv), Cs₂CO₃(1.3-3.0 equiv), CuI (0.05-0.2 equiv), Pd(OAc)₂ (0.05-0.2 equiv), dppf(0.05-0.2 equiv), and N,N-dimethylacetamide (DMA, 1-2 mL/mmol) wasdegassed with three vacuum/nitrogen cycles. The appropriatealkynyl-trimethylsilane (1.3-2.0 equiv) was added, and the reaction washeated at 80° C. under N₂ for 2-24 hours (until complete by TLC orLCMS). The reaction was allowed to cool to room temperature, dilutedwith ethyl acetate and water, and then filtered through Celite. Theaqueous layer was separated and extracted with ethyl acetate. Theorganics were combined, dried, filtered, concentrated, and then purifiedby silica gel column chromatography to give the alkynyl-indazole.

Note: Alternate bases include K₂CO₃ and CsF; Alternate ligands include1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride and Ph₃P; Alternatecatalysts include Pd(PPh₃)₄ and PdCl₂(PPh₃)₂; Alternate solvents includeTHF and pyrrolidine. Water content seems to impact the rate of thisreaction: when anhydrous Cs₂CO₃ and anhydrous solvent were used, 1%water (v/v with respect to solvent) was added to the reaction, and whenthe Cs₂CO₃ and/or solvent were not anhydrous, no water was added.

An alternate procedure has also been employed, especially withiodo-indazoles: The appropriate alkynyl-trimethylsilane (2.1 equiv) wasadded to a degassed solution of TBAF (2.0 equiv, 0.5M in THF). After5-30 min, the appropriate halo-indazole (1.0 equiv), CuI (0.05-0.3equiv), and Pd(PPh₃)₄ (0.05-0.2 equiv) were added. The reaction wasstirred at room temperature under N₂ for 2-24 hours (until complete byTLC or LCMS), then diluted with water, and extracted with an appropriatesolvent. The extracts were combined, dried, filtered, concentrated, andthen purified by silica gel column chromatography to give thealkynyl-indazole.

Note: Alternate catalysts include PdCl₂(PPh₃)₂; Cosolvents includetriethylamine and pyrrolidine; When employing bromo-heterocycles, thereaction temperature was increased (80-120° C.).

General Procedure C: Multi-Component Cross-Coupling of theAlkynyl-Indazoles.

A mixture of the appropriate alkynyl-indazole (1.0 equiv), aryl-iodide(3.0 equiv), aryl-boronic acid (3.0 equiv), K₂CO₃ (3.0 equiv), andN,N-dimethylformamide (DMF)/water (2:1, 50 mL/mmol) was degassed withthree vacuum/N₂ cycles and then heated at 45° C. After 10 min (or whenhomogenous), a solution of Pd(PhCN)₂Cl₂ (0.01 equiv) in DMF was added.The reaction was stirred at 45° C. for 4-24 h (until complete by TLC orLCMS), allowed to cool to room temperature, quenched with water, andthen extracted with ethyl acetate. The extracts were washed with water,washed with brine, dried, filtered, concentrated, and purified by silicagel chromatography to give the desired tetra-substituted alkene.

Note 1: In some instances, all chemicals were simply mixed at roomtemperature, degassed, and then heated. In other instances, the boronicacid was added last as a DMF/water solution.

Note 2: When incomplete conversion of alkynyl-indazole was observed(especially with ortho-substituted aryl-iodides), additionalaryl-iodide, aryl-boronic acid, and K₂CO₃ (1-3 equiv each) were added,and heating was continued for 8-24 h. In some instances, this wasrepeated multiple times to improve the conversion and yield.

General Procedure D: Alternate Multi-Component Cross-Coupling of theAlkynyl-Indazoles.

Step 1: Formation of bis(pinacolato)diboryl-alkene

A solution of the appropriate alkynyl-indazole (1.0 equiv),bis(pinacolato)diboron (1.01-1.02 equiv), Pt(PPh₃)₄ (0.0025-0.03 equiv;Note 1), and solvent (2 mL/mmol of dioxane, DME, 2-MeTHF, PhMe, or DMA;Note 2) was degassed with three vacuum/N₂ cycles and then heated at80-120° C. (Note 3) under N₂ for 1-8 h (until complete by TLC or LCMS).The reaction was allowed to cool to room temperature and then either 1)taken directly into Step 2; 2) concentrated to give a crude residue[usually a foam]; or 3) concentrated and purified by silica gelchromatography to give the pure bis(pinacolato)diboryl-alkene.

Note 1: Most commonly, 0.01 equivalents were utilized. Note 2: Mostcommonly, 2-MeTHF was utilized. Note 3: Most commonly, reactions wererefluxed.

Step 2: Cross-coupling of the bis(pinacolato)diboryl-alkene

A mixture of bis(pinacolato)diboryl-alkene (1.0 equiv), an appropriate4-iodoaryl-aldehyde (1.0 equiv), PdCl₂(PPh₃)₂ (0.02-0.1 equiv; Note 1),Cs₂CO₃ (1.3-3 equiv; Note 2), solvent (4 mL/mmol: dioxane, DME, 2-MeTHF,PhMe, DMA; Note 3 & 4), and water (0-3% v/v; Note 5) was stirredvigorously at 20-40° C. (Note 6) under N₂ (Note 7) for 1-24 h (untilcomplete by TLC or LCMS). The reaction was then either 1) taken directlyinto Step 3; or 2) processed to isolate the1-aryl-2-(pinacolato)boryl-alkene: [The reaction was diluted with ethylether (or ethyl acetate) and washed with water (1-3 times). The aqueousphases were back extracted with ethyl ether (or ethyl acetate). Theextracts were combined, dried, filtered, concentrated and then purifiedby silica gel chromatography].

Note 1: Most commonly, 0.1 equivalents were used. Alternate catalystsinclude PdCl₂(dppf). Note 2: Most commonly, 2 or 3 equivalents wereused. Water content of the Cs₂CO₃ affects this reaction, see Note 5.Note 3: Most commonly, 2-MeTHF was used. Note 4: When thebis(pinacolato)diboryl-alkene is brought into this step as a solutionfrom Step 1, solvent (2 mL/mmol) is added to make the final volume ofsolvent approximately 4 mL/mmol Note 5: Most commonly, anhydrous Cs₂CO₃and anhydrous solvent were used, so 1-2% water (v/v with respect tosolvent) was added to the reaction. When the Cs₂CO₃ and/or solvent werenot anhydrous, no water was added. Note 6: Most commonly, reactions wererun at room temperature. Note 7: In some instances, this reaction wasdegassed with three vacuum/N₂ cycles.

Step 3: Cross-coupling of the 1-aryl-2-(pinacolato)boryl-alkene

A mixture of 1-aryl-2-(pinacolato)boryl-alkene (1.0 equiv), anappropriate aryl-halide (1.3-2 equiv; Note 1), PdCl₂(PPh₃)₂ (0.02-0.1equiv; Note 2), solvent (4 mL/mmol: dioxane, DME, 2-MeTHF, DMSO; Notes 3& 4), and KOH (3-6M, 5-6 equiv; Note 5) was degassed with threevacuum/N₂ cycles and then heated at 80-100° C. (Note 6) under N₂ for1-24 h (until complete by TLC or LCMS). The reaction was allowed to coolto room temperature, diluted with ethyl ether (or ethyl acetate), andwashed with water (1-3 times). The aqueous phases were back extractedwith ethyl ether (or ethyl acetate). The extracts were combined, dried,filtered, concentrated and then purified by silica gel chromatography togive the desired tetra-substituted alkene.

Note 1: Most commonly, 1.5 equivalents of aryl-iodide were used. Note 2:Most commonly, 0.1 equivalents were used. Alternate catalysts includePdCl₂(dppf). Note 3: Most commonly, dioxane, DME, or 2-MeTHF was used.Note 4: When the 1-aryl-2-(pinacolato)boryl-alkene is brought into thisstep directly from Step 2, no additional solvent or PdCl₂(PPh₃)₂ wasadded. Only the aryl-halide and KOH are added. Note 5: Most commonly, 6equiv of KOH are used, and the aqueous solution of KOH is 4M or 6M. Forcompounds with sensitive functionality, K₂CO₃ (6 equiv, 4M aqueous) isused in place of KOH, and DMSO is used as either the sole solvent or aco-solvent. Note 6: Most commonly, reactions were refluxed.

General Procedure E: Olefination of the Tetrasubstituted-AlkeneAryl-Aldehydes

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 1.1 equiv) was added dropwiseto a mixture of the appropriate aryl-aldehyde (1.0 equiv),triethylphosphonoacetate (1.1-1.3 equiv), lithium chloride (2.0 equiv),and anhydrous acetonitrile (2 mL/mmol) at room temperature. Theresulting mixture was stirred for 1-4 h (until complete by TLC or LCMS)and then concentrated. Dichloromethane (or ethyl acetate or ether) wasadded, and the mixture was washed with water, washed with brine, dried,filtered, concentrated, and purified by silica gel column chromatographyto give the desired acrylic ester.

Note 1: In some instances, alternate phosphonate reagents were utilizedto give the desired acrylic ester. Note 2: Alternate reactionconditions: 1-2 equivalents of phosphonate in THF at −78° C. or 0° C.were treated with n-BuLi or NaH (1-2 equiv). Then aryl-aldehyde (1equiv) was added, and the reaction was continued at −78° C., 0° C., orroom temperature until the reaction was complete by TLC and/or LCMS.

General Procedure F: Removal of the Tetrahydropyran Protecting Groupfrom the Indazole.

A solution of HCl (Note 1) was added to a solution of the THP-protectedindazole (1.0 equiv) in ethanol (2-5 mL/mmol; Note 2) at roomtemperature. The mixture was heated at 70° C. (Note 3) for 2-8 h (untilcomplete by TLC or LCMS), allowed to cool to room temperature, andconcentrated to give a crude product that was either carried on directlyto the next step or purified by silica gel chromatography.

Note 1: Most commonly, 2M HCl in diethyl ether or 1.25M HCl in ethanolwere used. Most commonly, the volume of HCl solution used was 10% of thesolvent volume. Note 2: Most commonly, the concentration was 5 mL/mmolIn some instances, methanol or isopropanol were used. Note 3: In someinstances, the reaction was heated at 80° C. or reflux.

General Procedure G: Hydrolysis of the Acrylic Ester to the AcrylicAcid.

An aqueous solution of LiOH (2-20 equiv; Note 1) was added to a solutionof the appropriate ester (1.0 equiv) in ethanol/tetrahydrofuran (1:1, 10mL/mmol; Note 2) at room temperature, and the mixture was stirred for4-24 h (until complete by TLC or LCMS). A solution of HCl (1M aqueous)was added until the pH was 3 (Note 3). The mixture was diluted withwater and extracted with ethyl acetate (or dichloromethane or ether).The organic layer was washed with water, washed with brine, dried,filtered, concentrated, and purified by silica gel chromatography orpreparative-HPLC to give the desired acrylic acid.

Note 1: Most commonly, a 2M solution of aqueous LiOH was used, or theLiOH was dissolved in a minimum amount of water. In some instances, NaOHor KOH was used. Note 2: In some instances, a single solvent (ethanol,dioxane, or tetrahydrofuran) was used. Note 3: Alternate work-upprocedures have been employed including: i) the use of sat' d NH₄Cl inplace of aqueous HCl and ii) removal of the organic solvent by rotaryevaporation prior to acid quench.

Example 28 Preparation of Compound 1: (E)-Ethyl3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenypacrylate Step1: (E)-Ethyl3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

A solution of 5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(2.5 g, 9.83 mmol, Intermediate 3), iodobenzene (6 g, 29.5 mmol),(E)-(4-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)boronic acid (6.49 g, 29.5mmol), K₂CO₃ (4.08 g, 29.5 mmol), and N,N-dimethylformamide/water (2:1,492 mL) was degassed with 3 vacuum/N₂ cycles and then heated at 45° C.until it was a homogenous solution. A solution of Pd(PhCN)₂Cl₂ (38 mg,0.098 mmol) in N,N-dimethylformamide (0.5 mL) was added. The resultingmixture was stirred at 45° C. overnight. Upon completion, the reactionmixture was cooled down to room temperature, quenched with water (500mL), and extracted with ethyl acetate (3×500 mL). The combined organicswere washed with water, washed with brine, dried over sodium sulfate,filtered, and concentrated to give the crude product. This crudematerial was purified on a silica gel column eluted with 0-50% ethylacetate in hexanes affording the title compound as off-white foam (3.71g). LCMS: 423 [(M-THP+H)+H]⁺.

Step 2: (E)-Ethyl3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate

To a solution of (E)-ethyl3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate(3.5 g, 69 mmol) in ethyl alcohol (69 mL), HCl (6 mL, 2M in diethylether) was added at room temperature. The resulting mixture was thenheated at 70° C. for 2 h. Upon completion, the mixture was cooled downto room temperature and concentrated to give the crude product. Thiscrude material was purified on a silica gel column eluted with 0-100%ethyl acetate in hexanes affording an off-white solid (2.5 g). ¹H NMR(300 MHz, DMSO-d₆): δ 13.10 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.53(d, 1H), 7.48 (d, 1H), 7.39 (d, 2H), 7.27-7.11 (m, 6H), 6.89 (d, 2H),6.45 (d, 1H), 4.20 (q, 2H), 2.43 (q, 2H), 1.22 (t, 3H), 0.87 (t, 3H);LCMS: 423 (M+H)⁺.

Example 29 Preparation of Compound 2:(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid

To a solution of (E)-ethyl3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate (2.5g, 5.9 mmol; Compound 1) in THF-EtOH (1:1, 59 mL), an aqueous solutionof LiOH (2.8 g, 118 mmol; dissolved in a minimum amount of water) wasadded at room temperature. The resulting mixture was stirred overnight.The reaction was monitored by LCMS. Upon completion, 1N aqueous HCl wasadded until pH was 3. Then, the mixture was diluted with water andextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water, washed with brine, dried over sodium sulfate,filtered, and concentrated to give the crude product. This crudematerial was purified on a silica gel column eluted with 0˜20% methanolin dichloromethane affording the title compound as a pale yellow solid(1.9 g). ¹H NMR (300 MHz, DMSO-d₆): δ 13.11 (s, 1H), 12.30 (br, 1H),8.08 (s, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.43 (d, 1H), 7.37 (d, 2H),7.29-7.11 (m, 6H), 6.88 (d, 2H), 6.37 (d, 1H), 2.44 (q, 2H), 0.87 (t,3H); LCMS: 395 (M+H)⁺.

Compounds 3 to 89 were prepared from alkynyl-indazole intermediatesfollowing General Procedures C, F, & G. The alkynyl-indazoleintermediates have either i) been described herein or ii) were preparedfrom known or commercially available halo-indazoles following GeneralProcedures A & B.

Compounds 90 to 92 are intermediates from the synthesis of Compounds 3,12, &13.

Example 30 Preparation of Compound 93:(E)-3-(4-((E)-2-(3-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid

A 10-mL recovery flask equipped with a magnetic stir bar, a rubberseptum and N₂ inlet was charged with(E)-3-(4-((E)-1-(1H-indazol-5-yl)-2-(3-methoxyphenyl)but-1-en-1-yl)phenyl)acrylicacid (30 mg, 0.07 mmol, Compound 5) and DCM (1.4 mL). This solution wascooled down to 0° C. in an ice-bath. Then, BBr₃ (88 mg, 0.35 mmol) wasadded dropwise via a syringe. The reaction mixture was stirred at 0° C.for 1 h. Upon completion, the reaction was quenched with methanol (5 mL)at 0° C. The resulting mixture was concentrated under reduced pressureto give the crude product that was directly purified on a reversedphased C-18 column eluted with 40-100% acetonitrile in water in thepresence of 0.1% TFA affording the title compound as an off-white solid(11 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 13.11 (s, 1H), 12.32 (br, 1H),9.23 (s, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.52 (d, 1H), 7.45-7.35 (m,3H), 7.12 (d, 1H), 7.00 (t, 1H), 6.90 (d, 2H), 6.59-6.53 (m, 3H), 6.36(d, 1H), 2.37 (q, 2H), 0.89 (t, 3H); LCMS: 411 (M+H)⁺.

Example 31 Preparation of Compound 94:(E)-3-(4-((E)-2-(2-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid

A 10-mL recovery flask equipped with a magnetic stir bar, a rubberseptum and N₂ inlet was charged with (E)-ethyl3-(4-((E)-1-(1H-indazol-5-yl)-2-(2-methoxyphenyl)but-1-en-1-yl)phenyl)acrylate(145 mg, 0.32 mmol, an intermediate in the synthesis of Compound 12) inDCM (6 mL). This solution was cooled down to −78° C. in an IPA/dryice-bath. Then, BBr₃ (241 mg, 0.96 mmol) was added dropwise via asyringe. The reaction mixture was gradually warmed to 0° C. for 1 h.Upon completion, the reaction was quenched with methanol (5 mL) at 0° C.The resulting mixture was concentrated under reduced pressure to givethe crude product. Then, this crude product was dissolved in THF-EtOH(1:1, 6 mL), and aqueous LiOH (0.15 g, 6.4 mmol) was added at roomtemperature. The resulting mixture was stirred at this temperatureovernight. Reaction was monitored by LCMS. Upon completion, 1N aqueousHCl was added until pH was 3. Then, the mixture was diluted with waterand extracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (100 mL), washed with brine (50 mL), dried oversodium sulfate, filtered, and concentrated to give the crude product.This crude material was purified on a reversed phase C-18 column elutedwith 40-100% acetonitrile in water in the presence of 0.1% TFA affordingthe title compound. ¹H NMR (300 MHz, DMSO-d₆): δ 13.07 (s, 1H), 12.34(br, 1H), 9.33 (br, 1H), 8.08 (d, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.40(d, 1H), 7.32 (d, 2H), 7.15 (dd, 1H), 7.00-6.94 (m, 3H), 6.81-6.76 (m,2H), 6.57 (dt, 1H), 6.34 (d, 1H), 2.43-2.30 (m, 2H), 0.88 (t, 3H); LCMS:411 (M+H)⁺.

Compound 95 was prepared following the procedure outlined for Compound94.

Example 32 Preparation of Compound 96:(E)-3-(4-((E)-2-(3-Butoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid Step 1: (E)-Ethyl3-(4-((E)-2-(3-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

The title compound was prepared from Intermediate 3,3-iodophenol, and(E)-(4-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)boronic acid followingGeneral Procedure C.

Step 2: (E)-Ethyl3-(4-((E)-2-(3-butoxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

Potassium carbonate (53 mg, 0.38 mmol) was added to (E)-ethyl3-(4-((E)-2-(3-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate(101 mg, 0.19 mmol) in CH₃CN (1 mL). After stirring for 15 min,iodobutane (24 μL, 0.21 mmol) was added. The reaction was stirred at rtfor 15 h. Additional iodobutane (24 μL, 0.21 mmol) was added, and thereaction was stirred at 60° C. for 10 h and then at rt for 48 h. Thereaction was diluted with dichloromethane and filtered through celite.The filtrate was concentrated and purified by silica gel chromatography(0˜20% EtOAc in hexanes) to give 97 mg of (E)-ethyl3-(4-((E)-2-(3-butoxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylateas a white foam. ¹H NMR (400 MHz, DMSO-d₆): δ 8.12 (s, 1H), 7.73 (d,1H), 7.64 (s, 1H), 7.49 (d, 1H), 7.41 (d, 2H), 7.24 (dd, 1H), 7.12 (t,1H), 6.91 (d, 2H), 6.76 (d, 1H), 6.67-6.72 (m, 2H), 6.48 (d, 1H), 5.86(d, 1H), 4.15 (q, 2H), 3.86-3.94 (m, 1H), 3.72-3.80 (m, 3H), 2.38-2.46(m, 3H), 1.96-2.10 (m, 2H), 1.70-1.82 (m, 1H), 1.52-1.63 (m, 4H),1.31-1.37 (m, 2H), 1.22 (t, 3H), 0.85-0.92 (m, 6H); LCMS: 495[(M-THP+H)+H]⁺.

Step 3:(E)-3-(4-((E)-2-(3-Butoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid

The title compound was prepared from (E)-ethyl3-(4-((E)-2-(3-butoxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatefollowing General Procedures F and G. ¹H NMR (400 MHz, DMSO-d₆): δ 13.11(bs, 1H), 12.33 (bs, 1H), 8.08 (s, 1H), 7.64 (s, 1H), 7.54 (d, 1H), 7.43(d, 1H), 7.37 (d, 2H), 7.10-7.17 (m, 2H), 6.91 (d, 2H), 6.75 (d, 1H),6.66-6.72 (m, 2H), 6.37 (d, 1H), 3.78 (t, 2H), 2.43 (q, 2H), 1.52-1.60(m, 2H), 1.29-1.38 (m, 2H), 0.85-0.92 (m, 6H); LCMS: 467 (M+H)⁺.

Compound 97 was prepared following the procedure outlined for Compound96.

Example 33 Preparation of Compound 98:(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid Step 1: (E)-Ethyl3-(4-((E)-2-(2-(methylthio)phenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

The title compound was prepared from Intermediate 3,2-iodothioanisole,and (E)-(4-(3-ethoxy-3-oxoprop-1-en-1-yl)phenyl)boronic acid followingGeneral Procedure C. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.14 (s, 1H), 7.75 (d,1H), 7.72-7.65 (m, 1H), 7.44 (d, 1H), 7.35 (d, 2H), 7.29-7.24 (m, 1H),7.22-7.11 (m, 3H), 7.09-7.03 (m, 1H), 7.01 (d, 2H), 6.44 (d, 1H), 5.85(dd, 1H), 4.13 (q, 2H), 3.94-3.83 (m, 1H), 3.80-3.68 (m, 1H), 2.47-2.27(m, 6H), 2.09-1.93 (m, 2H), 1.83-1.69 (m, 1H), 1.67-1.52 (m, 2H), 1.20(t, 3H), 0.88 (t, 3H).

Step 2: (E)-Ethyl3-(4-((E)-2-(2-(methylsulfonyl)phenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

Potassium peroxymonosulfate (521 mg, 0.85 mmol) was added to a slurry of(E)-ethyl3-(4-((E)-2-(2-(methylthio)phenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate(156 mg, 0.28 mmol) in MeOH:H₂O (1:1, 6 mL) at room temperature, and thereaction was stirred overnight. DCM and water were added, and the layerswere separated. The aqueous layer was washed with DCM (×2). The organiclayers were combined, washed with water, washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude material was purified on asilica gel column eluted with 0-50% ethyl acetate in hexane affordingthe title compound. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.15 (s, 1H), 7.91 (d,1H), 7.77-7.71 (m, 2H), 7.49-7.46 (m, 3H), 7.41-7.31 (m, 4H), 7.01 (d,2H), 6.45 (d, 1H), 5.87 (dd, 1H), 4.12 (q, 2H), 3.92-3.85 (m, 1H),3.82-3.69 (m, 1H), 2.93 (s, 3H), 2.46-2.27 (m, 2H), 2.09-1.97 (m, 3H),1.85-1.67 (m, 1H), 1.63-1.51 (m, 2H), 1.18 (t, 3H), 0.83 (t, 3H). LCMS:501 [(M-THP+H)+H]⁺.

Step 3:(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid

The title compound was prepared from (E)-ethyl3-(4-((E)-2-(2-(methylsulfonyl)phenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatefollowing General Procedures F & G. ¹H NMR (DMSO-d₆, 300 MHz): δ 13.14(br s, 1H), 12.29 (br s, 1H), 8.11 (d, 1H), 7.92 (dd, 1H), 7.71 (s, 1H),7.66-7.54 (m, 2H), 7.53-7.44 (m, 2H), 7.42-7.33 (m, 3H), 7.26 (dd, 1H),7.01 (d, 2H), 6.34 (d, 1H), 2.94 (s, 3H), 2.42-2.30 (m, 2H), 0.83 (t,3H); LCMS: 473 (M+H)⁺.

Example 34 Preparation of Compound 99:(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-methylacrylicacid Step 1:(E)-4-(2-Phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde

The title compound was prepared from Intermediate 3, iodobenzene, and(4-formylphenyl)boronic acid following General Procedure C. LCMS: 353[(M-THP+H)+H]⁺.

Step 2: (E)-Ethyl2-methyl-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

To a suspension of NaH (80 mg, 2 mmol, 60% dispersion in mineral oil) inTHF (10 mL) at 0° C., ethyl 2-(diethoxyphosphoryl)propanoate (0.36 g,1.5 mmol) was added. The reaction was stirred at 0° C. for 1 h, and thena THF solution of(E)-4-(2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde(0.44 g, 1 mmol) was added. The resulting mixture was gradually warmedto room temperature and stirred overnight. The reaction mixture wasquenched with saturated ammonium chloride solution and extracted withEtOAc (2×100 mL). Combined organic layers were washed with water, brine,dried over sodium sulfate, filtered and concentrated to give the crudematerial as pale yellow oil. LCMS: 437 [(M-THP+H)+H]⁺.

Step 3:(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-methylacrylicacid

The title compound was prepared from (E)-ethyl2-methyl-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatefollowing General Procedures F & G. ¹H NMR (300 MHz, DMSO-d₆): δ 13.11(s, 1H), 12.55 (br, 1H), 8.08 (d, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.42(d, 1H), 7.21-7.11 (m, 8H), 6.90 (d, 2H), 2.40 (q, 2H), 1.92 (d, 3H),0.87 (t, 3H); LCMS: 409 (M+H)⁺.

Compounds 100 to 109 were prepared from the appropriate boronic acid orphosphonate following the procedures outlined for Compound 99 or GeneralProcedures C, E, F & G.

Example 35 Preparation of Compound 110: (E)-Ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatehydrochloride Step 1:(E)-4-(2-(2-Chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde

A round-bottom flask equipped with a magnetic stir bar, a refluxcondenser, internal thermometer, and a N₂ inlet was charged with5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50.0 g, 197mmol; Intermediate 3), bis(pinacolato)diboron (50.4 g, 199 mmol), andanhydrous 2-methyltetrahydrofuran (393 mL) followed by Pt(PPh₃)₄ (1.83g, 1.5 mmol). This mixture was degassed with three vacuum/N₂ cycles,heated at 83° C. (internal temperature; oil bath at 95° C.) for 5 hunder N₂, and then allowed to cool to room temperature.2-Methyltetrahydrofuran (393 mL), cesium carbonate (128.1 g, 393 mmol),and water (11.8 mL, 1.5% v/v) were added, and the reaction was cooled to4° C. 4-Iodobenzaldehyde (45.6 g, 197 mmol) and PdCl₂(PPh₃)₂ (6.90 g,9.8 mmol) were added, and the reaction was degassed with three vacuum/N₂cycles. The mixture was allowed to warm to room temperature and stirredovernight. Aqueous KOH solution (4M, 275 mL, 1100 mmol) and2-chloro-4-fluoroiodobenzene (70.6 g, 275 mmol) were added. The reactionwas degassed with 3 vacuum/N₂ cycles, heated at 75° C. (internaltemperature; oil bath at 90° C.) for 7 h under N₂, and then allowed tocool to room temperature. The layers were separated, and the organiclayer was washed with brine (800 mL), dried over sodium sulfate,filtered, and concentrated. The crude product was purified by silica gelchromatography (0-20% ethyl acetate in hexanes) to give the titlecompound (82.6 g, 7:1 mixture of regioisomers) as a pale yellow foam.Data for major isomer;(E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde:¹H NMR (300 MHz, DMSO-d₆): δ 9.82 (s, 1H), 8.15 (s, 1H), 7.78-7.71 (m,2H), 7.61 (d, 2H), 7.43-7.27 (m, 3H), 7.15 (m, 3H), 5.86 (dd, 1H),3.93-3.85 (m, 1H), 3.79-3.68 (m, 1H), 2.44-2.36 (m, 3H), 2.10-1.96 (m,2H), 1.81-1.67 (m, 1H), 1.63-1.53 (m, 2H), 0.92 (t, 3H);

LCMS: 405 [(M-THP+H)+H]⁺.

Step 2: (E)-Ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

A round-bottom flask equipped with a magnetic stir bar, an additionfunnel, and a N₂ inlet was charged with(E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde(82.6 g, 169 mmol), triethylphosphonoacetate (40.6 mL, 203 mmol),lithium chloride (14.5 g, 338 mmol), and anhydrous acetonitrile (338mL). The reaction was cooled to 0° C. and then degassed with threevacuum/N₂ cycles. A solution of DBU (27.8 mL, 186 mmol) in acetonitrile(60 mL) was added dropwise over 35 min, and then the ice water bath wasremoved. The reaction was stirred at room temperature for 1 h,concentrated, and then partitioned between dichloromethane (250 mL) andH₂O (250 mL). The layers were separated, and the organic layer waswashed with brine (400 mL), dried over sodium sulfate, filtered, andconcentrated. The crude product was passed through a silica gel column(300 g, 20% ethyl acetate in hexanes) and concentrated to give the titlecompound (89.6 g) as a pale yellow foam. ¹H NMR (300 MHz, DMSO-d₆): δ8.14 (s, 1H), 7.75 (d, 1H), 7.50-7.33 (m, 6H), 7.27 (dt, 1H), 7.14 (dt,1H), 6.95 (d, 2H), 6.48 (d, 1H), 5.86 (dd, 1H), 4.14 (q, 2H), 3.94-3.86(m, 1H), 3.78-3.70 (m, 1H), 2.45-2.34 (m, 3H), 2.06-1.95 (m, 2H),1.78-1.67 (m, 1H), 1.62-1.53 (m, 2H), 1.19 (t, 3H), 0.90 (t, 3H); LCMS:475 [(M-THP+H)+H]⁺.

Step 3: (E)-Ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatehydrochloride

A round-bottom flask equipped with a magnetic stir bar was charged with(E)-ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate(255.9 g, 457.8 mmol) and a solution of HCl (732 mL, 1.25 M in ethylalcohol). The reaction was heated at 80° C. for 2.5 h, allowed to coolto room temperature, and then concentrated to an orange gel. tert-Butylmethyl ether (2.3 L) was added. After stirring for 5 min, solids beganto precipitate. The mixture was stirred at room temperature for 2 h andthen filtered. The solids were washed with MTBE (700 mL) and dried togive the title compound (193 g) as an off-white solid. ¹H NMR (DMSO-d₆):δ 8.11 (s, 1H), 7.69 (s, 1H), 7.57-7.50 (m, 2H), 7.45-7.33 (m, 4H),7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.48 (d, 1H), 4.14 (q, 2H), 2.38 (q,2H), 1.19 (t, 3H), 0.90 (t, 3H); LCMS: 475 (M+H)⁺.

Example 36 Preparation of Compound 111:(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid

A round-bottom flask equipped with a magnetic stir bar was charged with(E)-ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatehydrochloride (198.5 g, 388 mmol; Compound 110) and ethyl alcohol (517mL). A solution of LiOH (27.9 g, 1164 mmol) in water (388 mL) was added,and the mixture was stirred at room temperature overnight. The ethylalcohol was removed by rotary evaporation, and the remaining solutionwas cooled to 0° C. and acidified with 2M aqueous HCl to pH 3.Dichloromethane (500 mL) was added, the mixture was stirred, and thenthe layers were separated. The organic layer was washed with water,washed with brine, dried over sodium sulfate, filtered, andconcentrated. The crude product was passed through a silica column (800g, 5% MeOH in DCM) and concentrated. The product was then dissolved inDCM (400 mL), and acetonitrile (500 mL) was added. Approximately 200 mLof DCM was removed by rotary evaporation (solids began to precipitate).Acetonitrile (550 mL) was added followed by water (25 mL). The mixturewas stirred at room temperature for 2 h. The solvent was decanted, andthen acetonitrile:DCM (10:1; 550 mL) was added. The mixture stirred atroom temperature for 1.5 h, the solvent was again decanted, and thenacetonitrile:DCM (10:1; 550 mL) was added. The mixture was again stirredat room temperature for 1.5 h and then filtered. The solids wereresuspended in acetonitrile:DCM (10:1; 550 mL), stirred at roomtemperature for 1.5 h, filtered, and washed to give the title compound(123.9 g) as an off-white powder. ¹H NMR (DMSO-d₆): δ 13.12 (s, 1H),12.34 (br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.44-7.33 (m,5H), 7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.38 (d, 1H), 2.34 (q, 2H), 0.90(t, 3H); LCMS: 447 (M+H)⁺.

Example 37 Preparation of Compound 112: (E)-Ethyl3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylateStep 1:(E)-4-(2-(2,4-Dichlorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde

A round-bottom flask equipped with a magnetic stir bar, a refluxcondenser, and a N₂ inlet was charged with5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (20.0 g, 78.6mmol; Intermediate 3), bis(pinacolato)diboron (20.17 g, 79.4 mmol),tetrakis(triphenylphosphine)platinum (O) (0.98 g, 0.8 mmol), andanhydrous 1,4-dioxane (160 mL). This mixture was degassed with threevacuum/N₂ cycles and refluxed for 4 h. The solution was then allowed tocool to room temperature, and 4-iodobenzaldehyde (18.25 g, 78.6 mmol),trans-dichloro(triphenylphosphine)palladium (II) (5.52 g, 7.9 mmol),cesium carbonate (51.24 g, 157.3 mmol), and 1,4-dioxane (160 mL) wereadded. This mixture was degassed with three vacuum/N₂ cycles, and thenwater (4.7 mL) was added. This mixture was stirred at room temperaturefor 6 h. 2,4-Dichloroiodobenzene (12.8 mL, 94.4 mmol) and 6M aqueous KOH(62.9 mL) were added, and the mixture was degassed with three vacuum/N₂cycles and refluxed for 4 h. Upon completion, the reaction mixture wasfiltered through a Celite/silica pad and washed with EtOAc. The filtratewas washed with water (600 mL), washed with brine (300 mL), dried oversodium sulfate, filtered, and concentrated. The crude product waspurified by silica gel chromatography (0˜20% ethyl acetate in hexanes)to give the title compound (27.2 g, 7:1 mixture of regioisomers) as ayellow foam. Data for major regioisomer: ¹H NMR (400 MHz, DMSO-d₆): δ9.83 (s, 1H), 8.16 (s, 1H), 7.77 (d, 1H), 7.73 (s, 1H), 7.65 (d, 2H),7.53 (d, 1H), 7.41-7.36 (m, 2H), 7.31-7.28 (m, 1H), 7.17 (d, 2H), 5.86(dd, 1H), 3.92-3.86 (m, 1H), 3.78-3.71 (m, 1H), 2.47-2.38 (m, 3H),2.10-1.96 (m, 2H), 1.81-1.71 (m, 1H), 1.64-1.58 (m, 2H), 0.94 (t, 3H);LCMS: 421 [(M-THP+H)+H]⁺.

Step 2: (E)-Ethyl3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

A round-bottom flask equipped with a magnetic stir bar, a rubber septum,and a N₂ inlet was charged with(E)-4-(2-(2,4-dichlorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde(26.7 g, 52.8 mmol), triethylphosphonoacetate (12.7 mL, 63.4 mmol),lithium chloride (4.53 g, 105.7 mmol), and anhydrous acetonitrile (106mL). A solution of DBU (8.7 mL, 58.1 mmol) in ACN (27 mL) was slowlyadded dropwise via addition funnel The resulting mixture was stirred atroom temperature for 4 h. Upon completion, the reaction was concentratedand redissolved in DCM. This solution was washed with water (300 mL),washed with brine (250 mL), dried over sodium sulfate, filtered andconcentrated. The crude product was purified by silica gelchromatography (0˜20% ethyl acetate in hexanes) to give the titlecompound (29.0 g) as a pale yellow foam. ¹H NMR (400 MHz, DMSO-d₆): δ8.14 (s, 1H), 7.75 (d, 1H), 7.72 (s, 1H), 7.54 (d, 1H), 7.48 (d, 1H),7.43 (d, 2H), 7.37-7.35 (m, 2H), 7.29-7.26 (m, 1H), 6.97 (d, 2H), 6.48(d, 1H), 5.86 (dd, 1H), 4.14 (q, 2H), 3.91-3.86 (m, 1H), 3.77-3.71 (m,1H), 2.48-2.35 (m, 3H), 2.06-1.96 (m, 2H), 1.78-1.71 (m, 1H), 1.62-1.55(m, 2H), 1.22 (t, 3H), 0.90 (t, 3H); LCMS: 491 [(M-THP+H)+H]⁺.

Step 3: (E)-Ethyl3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

A solution of HCl (5.0 mL, 2.0 M in diethyl ether) was added to asolution of (E)-ethyl3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate(3.0 g, 5.2 mmol) in ethyl alcohol (25 mL) at room temperature. Theresulting mixture was heated at 70° C. for 2 h. Upon completion, themixture was cooled down to room temperature and concentrated to give apale yellow solid. This crude material was dissolved in DCM and washedwith water (50 mL), washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated. The crude product was purified bysilica gel chromatography (0-100% ethyl acetate in hexanes) to give thetitle compound (2.37 g) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 13.17 (s, 1H), 8.11 (s, 1H), 7.69 (s, 1H), 7.58-7.52 (m,2H), 7.48 (d, 1H), 7.43 (d, 2H), 7.36-7.32 (m, 2H), 7.19 (dd, 1H), 6.97(d, 2H), 6.49 (d, 1H), 4.15 (q, 2H), 2.39 (q, 2H), 1.22 (t, 3H), 0.90(t, 3H); LCMS: 491 (M+H)⁺.

Example 38 Preparation of Compound 113:(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid

A solution of LiOH (0.23 g, 9.6 mmol) in water (3.2 mL) was added to asolution of (E)-ethyl3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate(2.37 g, 4.8 mmol; Compound 112) in EtOH (20 mL) at room temperature.The resulting mixture was stirred overnight. Upon completion, 1N aqueousHCl was added until the pH was 3. The mixture was diluted with water andextracted with ethyl acetate (2×25 mL). The combined organic layers werewashed with water (50 mL), washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated. The crude product was purified on apreparative reversed-phased HPLC column using 80-95% acetonitrile inwater in the presence of 0.1% TFA to give the title compound (1.3 g) asan off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.11 (s, 1H), 12.36(br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.57-7.53 (m, 2H), 7.44-7.35 (m,5H), 7.19 (dd, 1H), 6.97 (d, 2H), 6.39 (d, 1H), 2.39 (q, 2H), 0.90 (t,3H); LCMS: 463 (M+H)⁺.

Compounds 114 to 139 were prepared from alkynyl-indazole intermediatesfollowing General Procedures D, E, F, & G. The alkynyl-indazoleintermediates have either i) been described herein or ii) were preparedfrom known or commercially available halo-indazoles following GeneralProcedures A & B.

Example 39 Preparation of Intermediate 45: (E)-Ethyl3-(4-((Z)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-1-en-1-yl)phenyl)acrylateStep 1: (E)-Ethyl 3-(4-iodophenyl)acrylate

N-Iodosuccinimide (2.5 g, 11 mmol) was added to a suspension of4-(E-3-ethoxy-3-oxo-1-propen-1-yl)phenylboronic acid (2.2 g, 10 mmol) inCH₃CN (50 mL) at room temperature. The reaction was covered with foil,stirred for ˜26 hours, and then diluted with EtOAc. The resultingmixture was washed with water (2×100 mL), washed with sodium thiosulfate(100 mL), dried (MgSO₄), filtered, and concentrated. The crude materialwas purified by silica gel chromatography (0-50% EtOAc in hexanes) togive 2.6 g of (E)-ethyl 3-(4-iodophenyl)acrylate as a yellow oil. ¹H NMR(400 MHz, DMSO-d₆): δ 7.79 (d, 2H), 7.60 (d, 1H), 7.53 (d, 2H), 6.68 (d,1H), 4.19 (q, 2H), 1.26 (t, 3H); LCMS: 303 (M+H)⁺.

Step 2: (E)-Ethyl3-(4-((Z)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-1-en-1-yl)phenyl)acrylate

The title compound was be prepared from Intermediate 3 and (E)-ethyl3-(4-iodophenyl)acrylate following General Procedure D, Steps 1-2. ¹HNMR (400 MHz, DMSO-d₆): δ 8.09 (s, 1H), 7.70 (d, 1H), 7.58-7.63 (m, 3H),7.49 (s, 1H), 7.11 (d, 3H), 6.58 (d, 1H), 5.84 (dd, 1H), 4.18 (q, 2H),3.86-3.91 (m, 1H), 3.70-3.77 (m, 1H), 2.36-2.48 (m, 1H), 2.08-2.15 (m,2H), 1.95-2.08 (m, 2H), 1.70-1.81 (m, 1H), 1.56-1.62 (m, 2H), 1.25 (t,3H), 1.12 (s, 12H), 1.01 (t, 3H); LCMS: 473 [(M-THP+H)+H]⁺.

Compounds 140 to 144 were prepared from Intermediate 45 followingGeneral Procedures D (Step 3; K₂CO₃ modification), F, & G.

Example 40 Preparation of Compound 145:(E)-3-(4-((E)-2-(2-Chlorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid

To a mixture of(E)-3-(4-((E)-2-(2-chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid (80 mg, 0.19 mmol; Compound 14) and Cs₂CO₃ (0.15 g, 0.46 mmol) inDMF (3.8 mL) at room temperature, iodomethane (65 mg, 0.46 mmol) wasadded. The mixture was stirred at room temperature overnight, dilutedwith water, extracted with EtOAc, and concentrated to give the(E)-methyl3-(4-((E)-2-(2-chlorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate.This residue was redissolved in THF-MeOH (3.8 mL) and an aqueoussolution of LiOH (89 mg, 3.7 mmol; dissolved in a minimum amount ofwater) was added at room temperature. The reaction mixture was stirredovernight, quenched with 1N HCl, extracted with EtOAc, dried over sodiumsulfate, filtered and concentrated to give the crude material. Thiscrude product was purified on a RP-C18 column using 50-100% acetonitrilein water in the presence of 0.1% TFA to afford the title compound. ¹HNMR (300 MHz, DMSO-d₆): δ 12.28 (s, 1H), 8.07 (s, 1H), 7.67-7.64 (m,2H), 7.48-7.11 (m, 8H), 6.95 (d, 2H), 6.35 (d, 1H), 4.05 (s, 3H), 2.36(q, 2H), 0.90 (t, 3H). LCMS: 443 (M+H)⁺.

Example 41 Preparation of Compound 146:(E)-3-(4-((E)-2-Cyclobutyl-1-(1-methyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid Step 1: (E)-Ethyl3-(4-((E)-2-cyclobutyl-1-(1-methyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylate

Iodomethane (80 mg, 0.84 mmol) was added to a mixture of (E)-ethyl3-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylate(0.25 g, 0.56 mmol; intermediate in the preparation of Compound 84),K₂CO₃ (0.12 g, 0.84 mmol), and DMF (5.6 mL) at room temperature. Theresulting mixture was stirred overnight, diluted with water, andextracted with EtOAc. The extract was washed with water, washed withbrine, dried over sodium sulfate, filtered, concentrated, and thenpurified on a silica gel column using 0-50% EtOAc in hexanes to affordthe title compound. LCMS: 463 (M+H)⁺.

Step 2:(E)-3-(4-((E)-2-Cyclobutyl-1-(1-methyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid

The title compound was prepared from (E)-ethyl3-(4-((E)-2-cyclobutyl-1-(1-methyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylateas described in General Procedure G. ¹H NMR (400 MHz, DMSO-d₆): δ 12.26(s, 1H), 8.06 (s, 1H), 7.68-7.61 (m, 2H), 7.37 (d, 1H), 7.31-7.12 (m,8H), 6.92 (d, 2H), 6.36 (d, 1H), 4.09 (s, 3H), 3.46-3.39 (m, 1H),1.84-1.76 (m, 4H), 1.63-1.52 (m, 1H), 1.37-1.32 (m, 1H); LCMS: 435(M+H)⁺.

Compound 147 was prepared following the procedure outlined for Compound146.

Example 42 Preparation of Compound 148:(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1-(difluoromethyl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid

A solution of (E)-ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate(105, mg, 0.22 mmol; freebase of Compound 110) in DMF (1 mL) was addedto a suspension of sodium hydride (11 mg, 0.27 mmol) in DMF (1 mL). Themixture was stirred at room temperature for 1 h, and thendifluoroiodomethane was bubbled in for 10 min. The reaction mixture washeated at 80° C. for 3 h and cooled to room temperature.Difluoroiodomethane was bubbled in for additional 10 min, and themixture was heated for an additional 1.5 h. The reaction mixture wascooled to room temperature, diluted with ethyl acetate (50 mL), washed(2×25 mL H₂O), dried (Na₂SO₄), and concentrated under reduced pressure.The crude material was purified on a silica gel column to yield amixture containing the desired intermediate. LCMS: 525 (M+H)⁺. FollowingGeneral Procedure G, this intermediate gave the title compound. ¹H NMR(300 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.17 (t, 1H), 7.77 (s, 1H), 7.74 (d,1H), 7.45-7.35 (m, 5H), 7.20 (dd, 1H), 7.15 (dt, 1H), 7.00 (d, 2H), 6.38(d, 2H), 2.41 (q, 2H), 0.92 (t, 3H); LCMS: 497 (M+H)⁺.

Example 43 3x ERE MCF-7 Reporter Assay

MCF7 cells were maintained in RPMI 1640 supplemented with 10% FCS.Transcriptional assays were performed by seeding 100 μL of cells at adensity of 250,000 cells/mL into 96-well cell culture plates in RPMI1640 supplemented with 10% charcoal stripped serum and allowed to attachovernight. Cells were transiently transfected using Lipofectin (LifeTechnologies) according to the manufacturer's protocol. Triplicatetransfections were performed using 300 ng 3×ERE-TK-Luc (reportervector), 50 ng CMVpRL (normalization vector), and 130 ng pCMX (fillerDNA). Transfected cells were incubated overnight then treated withligand. For ER agonist assays, the compounds were serially diluted and50 μL of compound plus RPMI 1640 supplemented with charcoal strippedserum was added to the cells. For ER antagonist assays, the compoundswere serially diluted and 50 μL of compound with RPMI plus 17β-estradiolsupplemented with charcoal stripped serum were added to the cells. Thefinal 17β-estradiol concentration used in the antagonist assays was 0.1nM. Following 24 hour incubation the medium was removed and the cellswere lysed in 40 μL of lysis buffer (25 mM Tris Phosphate, 2 mM CDTA,10% Glycerol, 0.5% Triton X-100, 2 mM DTT). Firefly luciferase activitywas measured immediately following the addition of 40 μL luciferasebuffer (20 mM tricine, 0.1 mM EDTA, 1.07 mM (MgCo₃)₄ Mg(OH)₂.5H₂O, 2.67mM MgSO₄, 33.3 mM DTT, 270 μM Coenzyme A, 470 μM luciferin, 530 μM ATP).Renilla luciferase was measured following the addition of 40 μLcolelenterazine buffer (1.1 M NaCl, 2.2 mM Na₂EDTA, 0.22 M KxPO₄ (pH5.1), 0.44 mg/mL BSA, 1.3 mM NaN₃, 1.43 μM coelenterazine, final pHadjusted to 5.0).

Example 44 Breast Cancer Cell Viability Assays

MCF-7 cells were adjusted to a concentration of 20,000 cells per mL inRPMI containing 10% FBS and 20 mM HEPES. 16 microliters of the cellsuspension (320 cells) was added to each well of a 384 well plate, andthe cells were incubated overnight to allow the cells to adhere. Thefollowing day an eleven point, serial semilog dilution of each compoundwas added to the cells in 16 μL at a final concentration ranging from0.3-0.000003 μM. After 5 days' compound exposure, 16 μL of CellTiter-GLo(Promega, Madison Wis.) was added to the cells the relative luminescenceunits (RLUs) of each well was determined CellTiter-Glo added to 32 μL ofmedium without cells was used to obtain a background value. The Percentviability of each sample was determined as follows: (RLU sample-RLUbackground/RLU untreated cells-RLU background)×100=% viability.

Viability effects in additional ER+breast cancer cell lines, includingBT474, CAMA1, MDA-MB-361, ZR-75-1, T47D, can be profiled in assayssimilar to Example 44.

Example 45 Breast Cancer Cell ER-α In Cell Western Assay (SP1)

MCF-7 cells were adjusted to a concentration of 200,000 cells per mL inRPMI containing 10% charcoal-stripped FBS and 20 mM HEPES. 16microliters of the cell suspension (3200 cells) was added to each wellof a poly-D-lysine 384 well plate, and the cells were incubatedovernight to allow the cells to adhere. The following day an elevenpoint, serial semilog dilution of each compound was added to the cellsin 16 μL at a final concentration ranging from 0.3-0.000003 μM. At 4 or24 hr post compound addition, the cells were fixed (10% formalin in PBS)for 20 minutes. Cells were permeablized in PBS 0.1% Triton and blockedwith LICOR blocking buffer (50 μL1/well, 90′). The wells were thenincubated overnight at 4° C. with SP1 rabbit monoclonal Ab (ThermoScientific) diluted 1:1000 in LICOR blocking buffer/0.1% Tween-20. Wellswhich were treated with blocking buffer with Tween but no antibody wereused as a background control. Wells were washed with 0.1% Tween-20/PBSand then incubated in goat anti-rabbit IRDye™ 800CW (LICOR Inc.; 1:1000)and DRAQ5 DNA dye (1:2000 for 2 mM stock) diluted in LICOR blockingbuffer containing 0.1% Tween-20 and 0.01% SDS for 60 minutes. Cells werewashed (50 μl/well, 5′ each) in 0.1% Tween-20/PBS. Plates were scannedon a LICOR Odyssey infrared imaging system. Integrated intensities inthe 800 nm channel and 700 nm channel were measured to determine levelsof ER and DNA respectively. Percent ER levels were determined asfollows: (Integrated intensity 800 nm sample/integrated intensity 700 nmsample)/(Integrated intensity 800 nm untreated cells/integratedintensity 700 nm untreated cells)×100=% ER levels.

Effects on steady state levels of ER-α in additional ER+ breast cancercell lines, including BT474, CAMA1, MDA-MB-361, ZR-75-1, T47D, can beprofiled in assays similar to Example 45.

Illustrative biological data for representative compounds disclosedherein is presented in the following table:

TABLE 7 MCF7 MCF7 ER-α In Cell ER-α In Cell Viability Viability WesternWestern Assay Assay Assay Assay (SP1) Compound IC₅₀ Max Response (SP1)IC₅₀ Max Response 1 A + A ++ 2 A ++ A ++ 3 A ++ A ++ 4 A ++ A ++ 5 A ++A ++ 6 B ++ A ++ 7 A ++ A ++ 8 B ++ A ++ 9 A ++ A ++ 10 A ++ A ++ 11 A++ A ++ 12 A ++ A ++ 13 A ++ A ++ 14 A ++ A ++ 15 A ++ A ++ 16 A ++ A ++17 A ++ A ++ 18 A ++ A ++ 19 A ++ A ++ 20 A ++ A ++ 21 A ++ A ++ 22 A ++A ++ 23 A ++ A ++ 24 A ++ A ++ 25 A ++ A ++ 26 A ++ A ++ 27 A ++ A ++ 28A ++ A ++ 29 A ++ A ++ 30 A ++ A ++ 31 A ++ A ++ 32 A ++ A ++ 33 A ++ A++ 34 A ++ A ++ 35 A ++ A ++ 36 A ++ A ++ 37 A ++ A ++ 38 B ++ B ++ 39 B++ B ++ 40 B ++ B ++ 41 A ++ A ++ 42 A ++ A ++ 43 A ++ A ++ 44 A ++ A ++45 A ++ A ++ 46 B + B ++ 47 A ++ A ++ 48 A ++ A ++ 49 A ++ A ++ 50 A ++A ++ 51 A ++ A ++ 52 A ++ A ++ 53 A ++ A ++ 54 A ++ A ++ 55 A ++ A ++ 56A ++ A ++ 57 A ++ A ++ 58 A ++ A ++ 59 A ++ A ++ 60 A ++ A ++ 61 A ++ A++ 62 A ++ A ++ 63 A ++ A ++ 64 A ++ A ++ 65 A ++ A ++ 66 A ++ A ++ 67 A++ A ++ 68 A ++ A ++ 69 A ++ A ++ 70 A ++ A ++ 71 A ++ A ++ 72 A ++ A ++73 A ++ A ++ 74 A ++ A ++ 75 A ++ A ++ 76 A ++ A ++ 77 A ++ A ++ 78 A ++A ++ 79 A ++ A ++ 80 B ++ A ++ 81 B ++ A ++ 82 A ++ A ++ 83 A ++ A ++ 84A ++ A ++ 85 A ++ A ++ 86 A ++ A ++ 87 A ++ A ++ 88 A ++ A ++ 89 A ++ A++ 90 A + A ++ 91 A + — — 92 A + — — 93 A ++ A ++ 94 B ++ A ++ 95 A ++ A++ 96 A ++ A ++ 97 A ++ A ++ 98 A ++ A ++ 99 A ++ A ++ 100 A ++ A ++ 101A ++ A ++ 102 A ++ A ++ 103 B ++ A ++ 104 B ++ A ++ 105 A ++ A ++ 106 A++ A ++ 107 B ++ A ++ 108 A ++ A ++ 109 A ++ A ++ 110 A + A ++ 111 A ++A ++ 112 A + A ++ 113 A ++ A ++ 114 A ++ A ++ 115 A ++ A ++ 116 A ++ A++ 117 A ++ A ++ 118 A ++ A ++ 119 A ++ A ++ 120 A ++ A ++ 121 A ++ A ++122 A ++ A ++ 123 A ++ A ++ 124 A ++ A ++ 125 A ++ A ++ 126 A ++ A ++127 B + B + 128 A ++ A ++ 129 A ++ A ++ 130 A ++ A ++ 131 B ++ B ++ 132A ++ A ++ 133 B + B ++ 134 A ++ A ++ 135 A ++ A ++ 136 A ++ A ++ 137 A++ A ++ 138 A ++ A ++ 139 A ++ A ++ 140 A ++ A ++ 141 B ++ A ++ 142 A ++A ++ 143 B ++ A ++ 144 A ++ A ++ 145 A ++ A ++ 146 A ++ A ++ 147 A ++ A++ 148 A ++ A ++ A = single IC₅₀ ≦ 100 nM; B = single IC₅₀ > 100 nM; + =a single % value < 40%; ++ = a single % value ≧ 40%

Example 46 Ishikawa Uterine Cell Alkaline Phosphatase Assay

Subconfuent Ishikawa cells in a T225 are incubated 24 hours in anestrogen free basal medium (EFBM) consisting of DMEM:Ham's F-12 50:50phenol red free basal medium containing 5% Charcoal Dextran treated FBSand 20 mM HEPES. Cells are plated the following day in EFBM in clear 384well plates at a concentration of 2.5×10⁵ cells per mL, 16 μL per well(4000 cells per well). A 12 point semilog dilution of each compound iscarried out in DMSO and subsequently diluted in EFBM. An equal volume ofcompound in EFBM is added immediately after plating cells, and the cellsare incubated for 3 days. The cells are fixed with 5% formalin, andrinsed with PBS. Alkaline Phosphatase substrate 4-Nitrophenyl phosphatedisodium salt hexahydrate is added to a solution containing 2 mM MgCl₂,1 M diethanolamine, and adjusted to pH 9.0. The substrate solution isadded to the cell cultures (16 μL per well), and OD405 is measured in amultiwall plate spectrophotometer when the optical density at 405 nmwavelength of cells treated with 17β-estradiol in the concentrationrange of 1-30 nM reaches 1.0-1.2 absorbance units. Cells treated withDMSO alone serve as a background control. Percent activity in backgroundsubtracted samples is measured as follows: % activity=OD405 sample/OD405max of 17β-estradiol treated cells×100.

Example 47 Ovarian Cancer Cell Viability Assays

BG-1, cells were adjusted to a concentration of 20,000 cells per mL inRPMI containing 10% FBS and 20 mM HEPES. 16 microliters of the cellsuspension (320 cells) was added to each well of a 384 well plate, andthe cells were incubated overnight to allow the cells to adhere. Thefollowing day an eleven point, serial semilog dilution of each compoundwas added to the cells in 16 μL at a final concentration ranging from0.3-0.000003 μM. After 5 days' compound exposure, 16 μL of CellTiter-GLo(Promega, Madison Wis.) was added to the cells the relative luminescenceunits (RLUs) of each well was determined CellTiter-Glo added to 32 μL ofmedium without cells was used to obtain a background value. The Percentviability of each sample was determined as follows: (RLU sample-RLUbackground/RLU untreated cells-RLU background)×100=% viability.

Viability effects in additional ER+ovarian cancer cell lines, includingA1847, SKOV3, SW626, A2780, can be profiled in assays similar to Example47.

Example 48 Ovarian Cancer Cell ER-α In Cell Western Assay

BG-1 cells were adjusted to a concentration of 200,000 cells per mL inRPMI containing 10% charcoal-stripped FBS and 20 mM HEPES. 16microliters of the cell suspension (3200 cells) was added to each wellof a poly-D-lysine 384 well plate, and the cells were incubatedovernight to allow the cells to adhere. The following day an elevenpoint, serial semilog dilution of each compound was added to the cellsin 16 μL at a final concentration ranging from 0.3-0.000003 μM. At 4 or24 hr post compound addition, the cells were fixed (10% formalin in PBS)for 20 minutes. Cells were permeablized in PBS 0.1% Triton and blockedwith LICOR blocking buffer (50 μl/well, 90′). The wells were thenincubated overnight at 4° C. with ER1D5 (Santa Cruz Biotechnology)diluted 1:100 in LICOR blocking buffer/0.1% Tween-20. Wells which weretreated with blocking buffer with Tween but no antibody were used as abackground control. Wells were washed with 0.1% Tween-20/PBS and thenincubated in goat anti-mouse IRDye™ 800CW (LICOR Inc.; 1:1000) and DRAQ5DNA dye (1:2000 for 2 mM stock) diluted in LICOR blocking buffercontaining 0.1% Tween-20 and 0.01% SDS for 60 minutes. Cells were washed(50 μl/well, 5′ each) in 0.1% Tween-20/PBS. Plates were scanned on aLICOR Odyssey infrared imaging system. Integrated intensities in the 800nm channel and 700 nm channel were measured to determine levels of ERand DNA respectively. Percent ER levels were determined as follows:(Integrated intensity 800 nm sample/integrated intensity 700 nmsample)/(Integrated intensity 800 nm untreated cells/integratedintensity 700 nm untreated cells)×100=% ER levels.

Effects on steady state levels of ER-α in additional ER+ovarian cancercell lines, including A1847, SKOV3, SW626, A2780, can be profiled inassays similar to Example 48.

Other cancer cell lines contemplated for testing compounds describedherein include: ER-positive endometrial cell lines (Ishikawa, ECC1,HEC-1, EnCa-101) and ER-positive cervical cell lines (Caski, HeLa,SiHa).

Example 49 Breast Cancer Model; Xenograft Assay (MCF-7)

Time release pellets containing 0.72 mg 17-β Estradiol weresubcutaneously implanted into nu/nu mice. MCF-7 cells were grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells were spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells were subcutaneously injected (100 μL/animal) onthe right flank 2-3 days post pellet implantation. Tumor volume(length×width²/2) was monitored bi-weekly. When tumors reached anaverage volume of ˜200 mm³ animals were randomized and treatment wasstarted. Animals were treated with Vehicle or Compound daily for 4weeks. Tumor volume and body weight were monitored bi-weekly throughoutthe study. At the conclusion of the treatment period, plasma and tumorsamples were taken for pharmacokinetic and pharmacodynamic analyses,respectively.

Example 50 Tamoxifen-Resistant Breast Cancer Model; Xenograft Assay(MCF-7 Derivative)

Female nu/nu mice (with supplemental 17-β Estradiol pellets; 0.72 mg; 60day slow release) bearing MCF-7 tumors (mean tumor volume 200 mm³) weretreated with Tamoxifen (citrate) by oral gavage. Tumor volume(length×width²/2) and body weight were monitored twice weekly. Followinga significant anti-tumor response in which tumor volume remained static,evident tumor growth was first observed at approximately 100 days oftreatment. At 120 days of treatment, tamoxifen dose was increased.Rapidly growing tumors were deemed tamoxifen resistant and selected forin vivo passage into new host animals. Tumor Fragments (˜100 mm³/animal)from the tamoxifen resistant tumors were subcutaneously implanted intothe right flank of female nu/nu mice (with 17-β Estradiol pellets (0.72mg; 60 day slow release)). Passaged tumors were maintained underconstant Tamoxifen selection, and Tumor volume (length×width²/2) wasmonitored weekly. When tumor volume reached ˜150-250 mm³, animals wererandomized into treatment groups (mean tumor volume 200 mm³) andtamoxifen treatment was terminated (except for a tamoxifen control arm).Animals were treated with Vehicle or Compound daily for 4 weeks. Tumorvolume and body weight were monitored twice weekly for the duration ofthe study. At the conclusion of the treatment period; plasma and tumorsamples were taken for pharmacokinetic and pharmacodynamic analyses,respectively.

Example 51 Ovarian Cancer Model; Xenograft Assay (BG-1)

Time release pellets (0.72 mg 17-β Estradiol/60 days) weresubcutaneously implanted into female nu/nu mice. BG-1 cells were grownin DMEM Ham's F-12 50/50 containing 10% FBS, 10 mM Sodium Pyruvate, 10mM Non-Essential Amino Acids at 5% CO₂, 37° C. Cells were spun down andre-suspended in 50% DMEM Ham's F-12 (serum free) and 50% Matrigel at5×10⁷ cells/mL. BG-1 cells were subcutaneously injected (100 μL/animal)on the right flank 2-3 days post pellet implantation. Tumor volume(length×width²/2) was monitored bi-weekly. When tumors reached anaverage volume of ˜250 mm³ animals were randomized and treatment wasstarted. Animals were treated with Vehicle or Compound daily for 4weeks. Tumor volume and body weight were monitored bi-weekly throughoutthe study. At the conclusion of the treatment period; plasma and tumorsamples were taken for pharmacokinetic and pharmacodynamic analyses,respectively.

Example 52 Immature Uterine Wet Weight-Antagonist Mode

Female immature CD-IGS rats (21 days old upon arrival) were treated forthree days. Animals were dosed daily for three days. Vehicle or testcompound was administered orally by gavage followed 15 minutes later byan oral dose of 0.1 mg/kg Ethynyl Estradiol. On the fourth day 24 hoursafter dose, plasma was collected for pharmacokinetic analysisImmediately following plasma collection, the animals were euthanized andthe uterus was removed and weighed.

Example 53 Immature Uterine Wet Weight-Agonist Mode

Female immature CD-IGS rats (21 days old upon arrival) were treated forthree days. Animals were dosed daily for three days. Vehicle or testcompound was administered orally by gavage followed 15 minutes later bya second oral dose of vehicle. On the fourth day 24 hours after dose,plasma was collected for pharmacokinetic analysis Immediately followingplasma collection, the animals were euthanized and the uterus wasremoved and weighed.

Example 54 Breast Cancer Clinical Trial

Purpose: The purpose of this study is to assess the efficacy oftreatment of metastatic breast cancer with a compound of Formula (I), ora pharmaceutically acceptable salt thereof, collect information on anyside effects the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, may cause, and evaluate the pharmacokineticproperties of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

Intervention: Patients are administered 1-50 mg/kg of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, per day ortwice a day.

Outcome Measures: Primary Outcome Measures: The primary outcome measureis the patient's tumor response and/or disease control to a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, as first-and/or second-line treatment in patients with estrogen receptor (ER)positive metastatic breast cancer.

Secondary Outcome Measures: The second outcome measures are (a) anevaluation of the side-effects of a compound of Formula (I), or apharmaceutically acceptable salt thereof (b) an evaluation of thepharmacokinetic properties of a compound of Formula (I), or apharmaceutically acceptable salt thereof; (c) an evaluation of theproportion of patients that have complete or partial response or stabledisease at defined timepoint; (d) an evaluation of the time toprogression and overall survival of patients treated with a compound ofFormula (I), or a pharmaceutically acceptable salt thereof; and (e)biomarkers predictive of clinical response.

Detailed Description: Patients will be given a compound of Formula (I),or a pharmaceutically acceptable salt thereof, orally once or twice aday. Prior to each dosing cycle of a compound of Formula (I), or apharmaceutically acceptable salt thereof, a physical exam, blood workand assessment of any side effects will be performed. Every 12 weeks thepatient's cancer will be re-evaluated with either a CT scan or MRI todetermine whether the treatment is working. Participation in this studywill last until disease progression or unacceptable toxicity.

Eligibility: Female subjects, 18 years and older.

Inclusion Criteria: Histologically or cytologically confirmed diagnosisof invasive breast cancer, Stage IV disease. At least one measurabletarget lesion as defined by RECIST that has not been previously treatedwith local therapy. Post-menopausal status. ER positive breast cancer.HER2-negative breast cancer. Up to one prior hormonal therapy foradvanced or metastatic disease. ECOG performance status 0-1. Lifeexpectancy>12 weeks. Adequate liver and bone marrow function: AST<2.5×ULN; Bilirubin<1.5×ULN; ANC>1,500/ul; platelet count>100,000/ul;normal PT and PTT. At least 2 weeks since prior radiation and recoveredfrom treatment-related toxicity.

Exclusion Criteria: HER2-positive breast cancer. Prior chemotherapyregimen for metastatic disease. History of, or presence of brainmetastases. Concurrent investigational drug treatment. Prior bone marrowor stem cell transplant. History of other malignancy within the last 5years, not including curatively-treated carcinoma in situ of the cervixor non-melanoma skin cancer. Uncontrolled infection. Active bleeding, orhistory of bleeding requiring transfusion.

Active cardiac disease. Serious medical or psychiatric illness.

Example 55 Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 100 mg of acompound of Formula (I), or a water-soluble salt of a compound ofFormula (I), is dissolved in sterile water and then mixed with 10 mL of0.9% sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection

In another embodiment, the following ingredients are mixed to form aninjectable formulation: 1.2 g of a compound of Formula (I), or apharmaceutically acceptable salt thereof, 2.0 mL of sodium acetatebuffer solution (0.4 M), HCl (1 N) or NaOH (1 M) (q.s. to suitable pH),water (distilled, sterile) (q.s. to 20 mL). All of the aboveingredients, except water, are combined and stirred and if necessary,with slight heating if necessary. A sufficient quantity of water is thenadded.

Example 56 Oral Solution

To prepare a pharmaceutical composition for oral delivery, an aqueous20% propylene glycol solution is prepared. To this is added a sufficientamount of compound of Formula (I), or a pharmaceutically acceptable saltthereof, to provide a 20 mg/mL solution.

Example 57 Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 100-500 mg ofa compound of Formula (I), or a pharmaceutically acceptable saltthereof, is mixed with starch. The mixture is incorporated into an oraldosage unit such as a hard gelatin capsule, which is suitable for oraladministration. In another embodiment, 100-500 mg of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is placedinto Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin)and the capsule is closed.

Example 58 Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, 45% by weight ofmicrocrystalline cellulose, 5% by weight of low-substitutedhydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

Example 59 Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is mixedwith hydroxypropyl celluose, propylene glycol, isopropyl myristate andpurified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A method of alleviating at least one symptom of adisease or condition in a mammal or arresting the development of adisease or condition in a mammal, wherein the disease or condition isbreast cancer, ovarian cancer, endometrial cancer, prostate cancer,uterine cancer, bone cancer, colorectal cancer, cervical cancer, or lungcancer, comprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, orN-oxide thereof, to the mammal suffering from breast cancer, ovariancancer, endometrial cancer, prostate cancer, uterine cancer, bonecancer, colorectal cancer, cervical cancer, or lung cancer:

wherein, Z is —OH or —OR¹⁰; R² is C₁-C₄alkyl, C₁-C₄-fluoroalkyl,C₁-C₄deuteroalkyl, C₃-C₆cycloalkyl, or —C₁-C₄alkylene-W; W is hydroxy,halogen, CN, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy,or C₃-C₆cycloalkyl; each R³ is independently halogen, C₁-C₄alkyl, orC₁-C₄-fluoroalkyl; each R⁴ is independently halogen, —CN, —OR⁹,—S(═O)₂R¹⁰, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, or C₁-C₄hetero alkyl; each R⁵is independently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰, C₁-C₄alkyl,C₁-C₄-fluoroalkyl, or C₁-C₄heteroalkyl; R⁶ is H, C₁-C₄alkyl, or halogen;R⁷ is H, C₁-C₄alkyl, or halogen; R⁹ is H, C₁-C₆alkyl, C₁-C₆-fluoroalkyl,or C₃-C₆cycloalkyl; R¹⁰ is C₁-C₆alkyl; m is 0, 1, or 2; n is 0, 1, 2, 3,or 4; and p is 0, 1, or
 2. 2. A method of alleviating at least onesymptom of a disease or condition in a mammal or arresting thedevelopment of a disease or condition in a mammal, wherein the diseaseor condition is leiomyoma, uterine leiomyoma, or endometriosis,comprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, orN-oxide thereof, to the mammal suffering from leiomyoma, uterineleiomyoma, or endometriosis:

wherein, Z is —OH or —OR¹⁰; R² is C₁-C₄alkyl, C₁-C₄-fluoroalkyl,C₁-C₄deuteroalkyl, C₃-C₆cycloalkyl, or —C₁-C₄alkylene-W; W is hydroxy,halogen, CN, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy,or C₃-C₆cycloalkyl; each R³ is independently halogen, C₁-C₄alkyl, orC₁-C₄-fluoroalkyl; each R⁴ is independently halogen, —CN, —OR⁹,—S(═O)₂R¹⁰, C₁-C₄alkyl, C₁-C₄-fluoroalkyl, or C₁-C₄heteroalkyl; each R⁵is independently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰, C₁-C₄alkyl,C₁-C₄-fluoroalkyl, or C₁-C₄heteroalkyl; R⁶ is H, C₁-C₄alkyl, or halogen;R⁷ is H, C₁-C₄alkyl, or halogen; R⁹ is H, C₁-C₆alkyl, C₁-C₆-fluoroalkyl,or C₃-C₆cycloalkyl; R¹⁰ is C₁-C₆alkyl; m is 0, 1, or 2; n is 0, 1, 2, 3,or 4; and p is 0, 1, or
 2. 3. The method of claim 1, wherein: Z is —OH;R⁶ is H, —CH₃, F, or Cl; R⁷ is H, —CH₃, F, or Cl; each R³ isindependently halogen, C₁-C₄alkyl, or C₁-C₄-fluoroalkyl; each R⁴ isindependently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰, C₁-C₄alkyl,C₁-C₄fluoroalkyl, or C₁-C₄heteroalkyl; each R⁵ is independently halogen,C₁-C₄alkyl, or C₁-C₄-fluoroalkyl; m is 0 or 1; n is 0, 1, or 2; and p is0 or
 1. 4. The method of claim 3, wherein: R² is C₁-C₄alkyl,C₁-C₄-fluoroalkyl, C₁-C₄deuteroalkyl, C₃-C₆cycloalkyl, or—C₁-C₄alkylene-W; W is hydroxy, halogen, CN, C₁-C₄alkoxy, orC₃-C₆cycloalkyl.
 5. The method of claim 4, wherein: Z is —OH; R⁶ is H;R⁷ is H; m is 0; n is 0, 1, or 2; and p is O.
 6. The method of claim 1,wherein the compound of Formula (I) has the structure of Formula (II):

or is a pharmaceutically acceptable salt thereof.
 7. The method of claim6, wherein: each R³ is independently F, Cl, or —CH₃; each R⁴ isindependently halogen, —CN, —OH, —S(═O)₂CH₃, —S(═O)₂CH₂CH₃, —CH₃,—CH₂CH₃, —CF₃, —CH₂OH, —OCF₃, —OCH₃, or —OCH₂CH₃; each R⁵ isindependently F, Cl, or —CH₃; m is 0 or 1; n is 0, 1, or 2; and p is 0or
 1. 8. The method of claim 7, wherein: R² is —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃,—CH₂CF₃, —CD₃, —CH₂CD₃, —CD₂CD₃, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, —CH₂—W, or —CH₂CH₂—W; W is hydroxy, F, Cl, —CN, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl.
 9. The method of claim 6, wherein: R² is —CH₂CH₃; each R⁴is independently F, Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CF₃, —CH₂OH, —OCF₃,—OCH₃, or —OCH₂CH₃; m is 0; n is 0, 1, or 2; and p is O.
 10. The methodof claim 1, wherein the compound of Formula (I) is: (E)-Ethyl3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluorophenyl)-1-(1-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(3-methoxyphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-(Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-(Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-(Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(o-tolyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(m-tolyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(p-tolyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-methoxyphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(4-methoxyphenyl)but-1-en-1-yl)phenyl)acrylicacid;((E)-3-(4-((E)-2-(2-Chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Ethylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-(trifluoromethyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-3-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluoro-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,6-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,6-Dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4,4,4-Trideutero-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluoro-3-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(5-Fluoro-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,3-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,5-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-5-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-6-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(7-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(7-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(6-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(3-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(3-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Hydroxy-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-4-methoxy-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-3-methoxy-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(6-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-4-methyl-2-phenylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopentyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclohexyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-3-Cyclopropyl-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chlorophenyl)-2-cyclopropyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(6-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylhex-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-3-Cyclopentyl-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(7-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)-4-methylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-3,3-Difluoro-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Fluoro-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-3,3,3-Trifluoro-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Fluoro-1H-indazol-5-yl)-2-(4-fluoro-2-methylphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)-2-(4-fluoro-2-methylphenyl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Chloro-1H-indazol-5-yl)-2-(2-chloro-4-fluorophenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-2-(2-Chloro-4-fluorophenyl)-3,3-difluoro-1-(1H-indazol-5-yl)prop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-1-(4-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-2-(2-chloro-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Fluoro-2-(4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Fluoro-1-(4-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-5-methoxy-2-phenylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-6-methoxy-2-phenylhex-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)-3-methylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(3-(trifluoromethoxy)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclobutyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(3-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid; (E)-Ethyl3-(4-((E)-2-(4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate;(E)-Ethyl3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-methoxyphenyl)but-1-en-1-yl)phenyl)acrylate;(E)-Ethyl3-(4-((E)-1-(1H-Indazol-5-yl)-2-(4-methoxyphenyl)but-1-en-1-yl)phenyl)acrylate;(E)-3-(4-((E)-2-(3-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Butoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Butoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-methylacrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-3-methylphenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-methylphenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-chlorophenyl)acrylicacid;(Z)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-fluoroacrylicacid;(Z)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-chloroacrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-3-fluorophenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-fluorophenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-(trifluoromethyl)phenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-3-methoxyphenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-methoxyphenyl)acrylicacid; (E)-Ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatehydrochloride;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid; (E)-Ethyl3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-(trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclopropyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluoro-2-(trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-(1-(4-Fluoro-1H-indazol-5-yl)-2-(4-fluoro-2-(trifluoromethyl)phenyl)butyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-(trifluoromethyl)phenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-4-fluoro-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-4-fluoro-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-2-(2,4-dichlorophenyl)-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-2-cyclopropyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-methyl-5-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(4-methoxy-2-methylphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Fluoro-4-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-5-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Fluoro-4-(methylsulfonyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-3,3,4,4,4-pentadeutero-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(3-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-3-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-3,3,4,4,4-pentadeutero-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyano-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyano-4-(trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Cyano-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Cyano-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(5-Cyano-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyano-4-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chlorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclobutyl-1-(1-methyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid; or(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1-(difluoromethyl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid; or a pharmaceutically acceptable salt, or N-oxide thereof.
 11. Themethod of claim 2, wherein: Z is —OH; R⁶ is H, —CH₃, F, or Cl; R⁷ is H,—CH₃, F, or Cl; each R³ is independently halogen, C₁-C₄alkyl, orC₁-C₄-fluoroalkyl; each R independently halogen, —CN, —OR⁹, —S(═O)₂R¹⁰,C₁-C₄alkyl, C₁-C₄fluoroalkyl, or C₁-C₄heteroalkyl; each R⁵ isindependently halogen, C₁-C₄alkyl, or C₁-C₄-fluoroalkyl; m is 0 or 1; nis 0, 1, or 2; and p is 0 or
 1. 12. The method of claim 11, wherein: R²is C₁-C₄alkyl, C₁-C₄-fluoroalkyl, C₁-C₄deuteroalkyl, C₃-C₆cycloalkyl, or—C₁-C₄alkylene-W; W is hydroxy, halogen, CN, C₁-C₄alkoxy, orC₃-C₆cycloalkyl.
 13. The method of claim 12, wherein: Z is —OH; R⁶ is H;R⁷ is H; m is 0; n is 0, 1, or 2; and p is O.
 14. The method of claim 2,wherein the compound of Formula (I) has the structure of Formula (II):

or is a pharmaceutically acceptable salt thereof.
 15. The method ofclaim 14, wherein: each R³ is independently F, Cl, or —CH₃; each R⁴ isindependently halogen, —CN, —OH, —S(═O)₂CH₃, —S(═O)₂CH₂CH₃, —CH₃,—CH₂CH₃, —CF₃, —CH₂OH, —OCF₃, —OCH₃, or —OCH₂CH₃; each R⁵ isindependently F, Cl, or —CH₃; m is 0 or 1; n is 0, 1, or 2; and p is 0or
 1. 16. The method of claim 15, wherein: R² is —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃,—CH₂CF₃, —CD₃, —CH₂CD₃, —CD₂CD₃, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, —CH₂—W, or —CH₂CH₂—W; W is hydroxy, F, Cl, —CN, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl.
 17. The method of claim 14, wherein: R² is —CH₂CH₃; eachR⁴ is independently F, Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CF₃, —CH₂OH, —OCF₃,—OCH₃, or —OCH₂CH₃; m is 0; n is 0, 1, or 2; and p is O.
 18. The methodof claim 2, wherein the compound of Formula (I) is: (E)-Ethyl3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylate;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluorophenyl)-1-(1-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(3-methoxyphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-(Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-(Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-(Hydroxymethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(o-tolyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(m-tolyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(p-tolyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-methoxyphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(4-methoxyphenyl)but-1-en-1-yl)phenyl)acrylicacid;((E)-3-(4-((E)-2-(2-Chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Chlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Ethylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-(trifluoromethyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-3-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluoro-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,6-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,6-Dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4,4,4-Trideutero-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluoro-3-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(5-Fluoro-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,3-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,5-Difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-5-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-6-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(7-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(7-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(6-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(3-Methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(3-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Hydroxy-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-4-methoxy-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-3-methoxy-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(6-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-4-methyl-2-phenylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Chloro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopentyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclohexyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-3-methyl-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-3-Cyclopropyl-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chlorophenyl)-2-cyclopropyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(6-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylhex-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-3-Cyclopentyl-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(7-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)-4-methylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-3,3-Difluoro-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Fluoro-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-3,3,3-Trifluoro-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Fluoro-1H-indazol-5-yl)-2-(4-fluoro-2-methylphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)-2-(4-fluoro-2-methylphenyl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(4-Chloro-1H-indazol-5-yl)-2-(2-chloro-4-fluorophenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((Z)-2-(2-Chloro-4-fluorophenyl)-3,3-difluoro-1-(1H-indazol-5-yl)prop-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-1-(4-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Chloro-2-(2-chloro-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Fluoro-2-(4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-4-Fluoro-1-(4-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-5-methoxy-2-phenylpent-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-6-methoxy-2-phenylhex-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)-3-methylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(3-(trifluoromethoxy)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclobutyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(3-Fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid; (E)-Ethyl3-(4-((E)-2-(4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate;(E)-Ethyl3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-methoxyphenyl)but-1-en-1-yl)phenyl)acrylate;(E)-Ethyl3-(4-((E)-1-(1H-Indazol-5-yl)-2-(4-methoxyphenyl)but-1-en-1-yl)phenyl)acrylate;(E)-3-(4-((E)-2-(3-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-RE)-2-(2-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-RE)-2-(4-Hydroxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Butoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Butoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-methylacrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-3-methylphenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-methylphenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-chlorophenyl)acrylicacid;(Z)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-fluoroacrylicacid;(Z)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-chloroacrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-3-fluorophenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-fluorophenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-(trifluoromethyl)phenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-3-methoxyphenyl)acrylicacid;(E)-3-(4-((Z)-1-(1H-Indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-methoxyphenyl)acrylicacid; (E)-Ethyl3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylatehydrochloride;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid; (E)-Ethyl3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-(trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclopropyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Fluoro-2-(trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-(1-(4-Fluoro-1H-indazol-5-yl)-2-(4-fluoro-2-(trifluoromethyl)phenyl)butyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-(trifluoromethyl)phenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-4-fluoro-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-4-fluoro-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-2-(2,4-dichlorophenyl)-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclopropyl-2-(2,4-dichlorophenyl)-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-methylphenyl)-2-cyclopropyl-1-(1H-indazol-5-yl)vinyl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(2-methyl-5-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(4-methoxy-2-methylphenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Fluoro-4-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-5-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Fluoro-4-(methylsulfonyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-3,3,4,4,4-pentadeutero-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-1-(1H-Indazol-5-yl)-2-(3-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-3-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-3,3,4,4,4-pentadeutero-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Chloro-2-cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyano-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyano-4-(trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(3-Cyano-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(4-Cyano-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(5-Cyano-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Cyano-4-methoxyphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chlorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid;(E)-3-(4-((E)-2-Cyclobutyl-1-(1-methyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylicacid;(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid; or(E)-3-(4-((E)-2-(2-Chloro-4-fluorophenyl)-1-(1-(difluoromethyl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylicacid; or a pharmaceutically acceptable salt, or N-oxide thereof.